Nitrogenous heterocyclic compounds

ABSTRACT

The present invention relates to nitrogen-containing heterocyclic compounds represented by formula (I):                    
     wherein W represents 1,4-piperazinediyl, etc.; U represents NR 1 R 2  (wherein R 1  represents a hydrogen atom, a substituted or unsubstituted alkyl group, etc.; and R 2  represents a hydrogen atom, etc. ), OR 4 , or SR 5 ; V represents an oxygen atom, a sulfur atom, N—R 6 , or CR 7 R 8 , at least one of X, Y and Z represents a nitrogen atom, and the others are the same or different, and each represents a nitrogen atom or C—R A ; and D 1 , D 2 , D 3  and D 4  each independently represent C—R B , a nitrogen atom, an oxygen atom, a sulfur atom, etc., optional adjoining two among D 1  to D 4  are combined to represent a nitrogen atom, N—R 2A , an oxygen atom, a sulfur atom, etc., or optional adjoining two selected from D 1  to D 4  represent C—R B″  (wherein two R B″ s are combined to represent substituted or unsubstituted alicyclic alkene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, etc.; or pharmaceutically acceptable salts thereof.

TECHNICAL FIELD

The present invention relates to nitrogen-containing heterocycliccompounds or pharmaceutically acceptable salts thereof which have anactivity of inhibiting phosphorylation of a platelet-derived growthfactor (PDGF) receptor and are useful in treating cell proliferativediseases, such as arteriosclerosis, vascular re-obstruction disease,cancers, glomerulonephritis, and the like.

BACKGROUND ART

It is known that PDGF functions as an advancing factor upon cellproliferative diseases, such as arteriosclerosis, vascularre-obstruction after percutaneous transluminal coronary angioplasty orbypass angioplasty, cancers, glomerulonephritis, glomerulosclerosis,psoriasis, articular rheumatism, and the like [Cell, 46: 155-169 (1986),Science, 253: 1129-1132 (1991), Nihon Rinsho, 50: 3038-3045 (1992),Nephrol Dial Transplant, 10: 787-795 (1995), Kidney International, 43(Suppl. 39): 86-89 (1993), Journal of Rheumatology, 21: 1507-1511(1994), Scandinavian Journal of Immunology, 27: 285-294 (1988), etc.].

Regarding nitrogen-containing heterocyclic compounds useful asmedicaments, for example,N,N-dimethyl-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazine carboxamideis disclosed as a bronchodilator in South African Patent 67 06512(1968). Also, pyrrolo[3,2-d]pyrimidine derivatives are disclosed inKhimiko-Farmatsveticheskij Zhurnal, 16: 1338-1343 (1982) asantibacterial agents, quinoline derivatives having benzodiazepinereceptor agonistic activity are disclosed in Pharmacology Biochemistryand Behavior, 53: 87-97 (1996) and European Journal of MedicinalChemistry, 31: 417-425 (1996), and quinoline derivatives useful asanti-parasitic agents are disclosed in Indian Journal of Chemistry, 26B:550-555 (1987).

Also, regarding PDGF receptor phosphorylation inhibitors, bismono- andbicyclic aryl and heteroaryl compounds are disclosed in WO 92/20642, andquinoxaline derivatives in Cancer Research, 54: 6106 (1994), pyrimidinederivatives in Japanese Published Unexamined Patent Application No.87834/94, quinoline derivatives and quinazoline derivatives in WO97/17329, pyrido[2,3-d]pyrimidine derivatives in J. Med. Chem., 40: 2296(1997), etc. and selenium derivatives in J. Med. Chem., 40: 413 (1997).

Inhibitors of phosphorylation of epidermal growth factor (EGF) receptorfamily are disclosed, for example, in Japanese Published UnexaminedPatent Application No. 208911/93, WO 96/09294, WO 96/31510 and WO97/13771. Tricyclic system nitrogen-containing heterocyclic compoundsdisclosed in WO 95/19970 and pyridopyrimidine derivatives disclosed inJ. Med. Chem., 39: 1823 (1996), for example, are known as compoundshaving the activity inhibiting phosphorylation of a receptor of EGFwhich is a tyrosine kinase. Also, as inhibitors of phosphorylation of anEGF receptor or EGF receptor family, pyrimidopyrimidine derivatives aredisclosed in J. Med. Chem., 40: 1820 (1997), pyrrolo- andpyrazoloquinazoline derivatives are disclosed in J. Med. Chem., 40: 1519(1997), and pyrrolopyrimidine derivatives are disclosed in WO 96/40142,WO 97/02266, WO 97/27199, EP 682027, etc. In addition, inhibitors ofphosphorylation of EGF receptor family are disclosed in JapanesePublished Unexamined Patent Application No. 208911/93, WO 96/09294, WO96/31510, WO 97/13771, etc. All of these compounds are ring-fusedpyrimidine derivatives and have a structure in which a simple aminogroup such as a substituted anilino group, an alkoxy group or the likeare linked to the 4-position of the pyrimidine ring.

On the other hand, in the compounds disclosed in the present invention,a structure, such as urea, thiourea, guanidine, amidine, or the like, islinked to a position corresponding to the 4-position of pyrimidine, viasubstituted or unsubstituted piperazine or homopiperazine, and such astructure is not known as to substances having the activity ofinhibiting phosphorylation of EGF receptors and the like.

DISCLOSURE OF THE INVENTION

The present invention relates to a nitrogen-containing heterocycliccompound represented by formula (I):

wherein W represents 1,4-piperazinediyl or 1,4-homopiperazinediyl inwhich carbon atoms on the ring may be substituted with 1 to 4 alkylgroups which are the same or different;

U represents NR¹R² (wherein R¹ represents a hydrogen atom, a substitutedor unsubstituted alkyl group, a substituted or unsubstituted alicyclicalkyl group, a substituted or unsubstituted alicyclic heterocyclicgroup, a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a substituted or unsubstituted aryl group,a substituted or unsubstituted aralkyl group, a substituted orunsubstituted heteroaryl group, or a substituted or unsubstitutedheteroarylalkyl group; and R² represents a hydrogen atom, a substitutedalkyl group, a substituted or unsubstituted alicyclic alkyl group, asubstituted or unsubstituted alicyclic heterocyclic group, a substitutedor unsubstituted alkenyl group, a substituted or unsubstituted alkynylgroup, a substituted or unsubstituted aryl group, a substituted orunsubstituted aralkyl group, a substituted or unsubstituted heteroarylgroup, a substituted or unsubstituted heteroarylalkyl group, CQR^(1A)(wherein Q represents an oxygen atom or a sulfur atom; and R^(1A) hasthe same meaning as R¹ described above), or SO₂R³ (wherein R³ representsa substituted or unsubstituted alkyl group, a substituted orunsubstituted alicyclic alkyl group, a substituted or unsubstitutedalicyclic heterocyclic group, a substituted or unsubstituted alkenylgroup, a substituted or unsubstituted alkynyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted aralkyl group,a substituted or unsubstituted heteroaryl group, or a substituted orunsubstituted heteroarylalkyl group)), OR⁴ (wherein R⁴ has the samemeaning as R³ described above), or SR⁵ (wherein R⁵ has the same meaningas R³ described above);

V represents an oxygen atom, a sulfur atom, N—R⁶ (wherein R⁶ has thesame meaning as R¹ described above or represents a cyano group, ahydroxyl group, a nitro group, a carbamoyl group, COOR^(3A) (whereinR^(3A) has the same meaning as R³ described above), CQ^(A)R^(1B)(wherein Q^(A) has the same meaning as Q described above, and R^(1B) hasthe same meaning as R¹ described above), or SO₂R^(3B) (wherein R^(3B)has the same meaning as R³ described above)), or CR⁷R⁸ (wherein R⁷and R⁸are the same or different and each represents a hydrogen atom, a cyanogroup, a nitro group, COOR^(3C) (wherein R^(3C) has the same meaning asR³ described above), or SO₂R^(3D) (wherein R^(3D) has the same meaningas R³ described above)), with the proviso that, when R¹ is hydrogen, R⁶and R² may be exchanged, V may represent N—R² (wherein R² has the samemeaning as defined above), and R² may represent R⁶ (wherein R⁶ has thesame meaning as defined above), and when U is OR⁴ or SR⁵, V representsN—R⁶ or CR⁷R⁸,

at least one of X, Y and Z represents a nitrogen atom, and the othersare the same or different, and each represents a nitrogen atom orC—R^(A) <wherein R^(A) has the same meaning as R¹ defined above, orrepresents a halogen atom, a cyano group, a nitro group, NR⁹R¹⁰ {whereinR⁹ and R¹⁰ are the same or different, and each has the same meaning asR¹ described above, or represents SO₂R^(3E) (wherein R^(3E) has the samemeaning as R³ described above) or CQ^(B)R¹¹ (wherein Q^(b) has the samemeaning as Q described above; and R¹¹ has the same meaning as R¹described above, or represents OR^(3F) (wherein R^(3F) has the samemeaning as R³ described above) or NR^(1C)R^(1D) (wherein R^(1C) andR^(1D) are the same or different, and each has the same meaning as R¹described above, or R^(1C) and R^(1D) are combined to represent asubstituted or unsubstituted nitrogen-containing heterocyclic group)),or R⁹ and R¹⁰ are combined to represent a substituted or unsubstitutednitrogen-containing heterocyclic group}, CQ^(C)R^(11A) (wherein Q^(C)has the same meaning as Q described above; and R^(11A) has the samemeaning as R¹¹ described above), OR¹² {wherein R¹² has the same meaningas R¹ described above, or represents CQ^(D)R¹³ (wherein Q^(D) has thesame meaning as Q described above; and R¹³ has the same meaning as R¹described above, or represents OR^(3G) (wherein R^(3G) has the samemeaning as R³ described above), SR^(3H) (wherein R^(3H) has the samemeaning as R³ described above), or NR^(1E)R^(1F) (wherein R^(1E) andR^(1F) are the same or different, and each has the same meaning as R¹described above, or R^(1E) and R^(1F) are combined to represent asubstituted or unsubstituted nitrogen-containing heterocyclic group)),or SO₂R^(3I) (wherein R^(3I) has the same meaning as R³ describedabove)}, SR^(1G) (wherein R^(1G) has the same meaning as R¹ describedabove), SOR^(3J) (wherein R^(3J) has the same meaning as R³ describedabove) or SO₂R¹⁴ (wherein R¹⁴ has the same meaning as R³ describedabove, or represents OR^(1H) (wherein R^(1H) has the same meaning as R¹described above) or NR^(1I)R^(1J) (wherein R^(1I) and R^(1J) are thesame or different, and each has the same meaning as R¹ described above,or R^(1I) and R^(1J) are combined to represent a substituted orunsubstituted nitrogen-containing heterocyclic group))>, and

(1) when V represents N—R⁶ or CR⁷R⁸, and U represents NR¹R², OR⁴, orSR⁵,

D¹, D², D³ and D⁴ each independently represent C—R^(B) (wherein R^(B)has the same meaning as R^(A) described above), a nitrogen atom, anoxygen atom, or a sulfur atom; or optional adjoining two among D¹ to D⁴may be combined to represent a nitrogen atom, N—R^(2A) (wherein R^(2A)has the same meaning as R² described above, or represents an alkyl groupor CQ^(E)NHR^(3K) (wherein Q^(E) has the same meaning as Q describedabove; and R^(3K) has the same meaning as R³ described above)), anoxygen atom, or a sulfur atom, and the remains among D¹ to D⁴ mayrepresent C—R^(B′) (wherein R^(B′) has the same meaning as R^(A)described above), N—R^(2A′) (wherein R^(2A′) has the same meaning asR^(2A) described above), or a nitrogen atom; and in these two cases, theoptional adjoining two selected from D¹ to D⁴ may represent C—R^(B″)(wherein two R^(B″)s, together with the two adjoining carbon atoms,represent substituted or unsubstituted alicyclic alkene, substituted orunsubstituted pyrrole, substituted or unsubstituted pyrazole,substituted or unsubstituted imidazole, substituted or unsubstitutedimidazol-2-one, substituted or unsubstituted imidazole-2-thione,substituted or unsubstituted triazole, substituted or unsubstitutedfuran, substituted or unsubstituted 1,3-dioxole, substituted orunsubstituted 1,4-dioxene, substituted or unsubstituted thiophene,substituted or unsubstituted oxazole, substituted or unsubstitutedoxadiazole, substituted or unsubstituted isoxazole, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted thiadiazole, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrazine, substituted orunsubstituted pyrimidine, substituted or unsubstituted pyridazine,substituted or unsubstituted triazine, substituted or unsubstitutedtetrazine, or substituted or unsubstituted benzene), and

(2) when V represents an oxygen atom or a sulfur atom, and U representsNR¹R²,

(2-1)

at least one of D¹ to D⁴ represents a nitrogen atom, an oxygen atom or asulfur atom; optional adjoining two among D¹ to D⁴ are combined torepresent a nitrogen atom, N—R^(2B) (wherein R^(2B) has the same meaningas R² described above), or an oxygen atom; or D² and D³ are combined torepresent a sulfur atom; and in these three cases, the remains among D¹to D⁴ represent a nitrogen atom, N—R^(2B′) (wherein R^(2B′) has the samemeaning as R² described above), an oxygen atom, a sulfur atom, orC—R^(C) (wherein the R^(C)s each independently have the same meaning asR^(A) described above, or optional two R^(C)s' adjoining carbon atoms ofwhich are adjacent, together with the two adjoining carbon atoms, mayrepresent substituted or unsubstituted alicyclic alkene, substituted orunsubstituted pyrrole, substituted or unsubstituted pyrazole,substituted or unsubstituted imidazole, substituted or unsubstitutedimidazol-2-one, substituted or unsubstituted imidazole-2-thione,substituted or unsubstituted triazole, substituted or unsubstitutedfuran, substituted or unsubstituted 1,3-dioxole, substituted orunsubstituted 1,4-dioxene, substituted or unsubstituted oxazole,substituted or unsubstituted oxadiazole, substituted or unsubstitutedisoxazole, substituted or unsubstituted thiophene, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted thiadiazole, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrazine, substituted orunsubstituted pyrimidine, substituted or unsubstituted pyridazine,substituted or unsubstituted triazine, substituted or unsubstitutedtetrazine, or substituted or unsubstituted benzene),

(2-2)

D¹ and D² are combined to represent a sulfur atom; D³ representsC—R^(C′) (wherein R^(C′) has the same meaning as R^(A) described above);and D⁴ represents a nitrogen atom, or D³ and D⁴ represent C—R^(C″)(wherein R^(C″)s, together with two adjoining carbon atoms, representsubstituted or unsubstituted alicyclic alkene, substituted orunsubstituted pyrrole, substituted or unsubstituted pyrazole,substituted or unsubstituted imidazole, substituted or unsubstitutedimidazol-2-one, substituted or unsubstituted imidazole-2-thione,substituted or unsubstituted triazole, substituted or unsubstitutedfuran, substituted or unsubstituted 1,3-dioxole, substituted orunsubstituted 1,4-dioxene, substituted or unsubstituted oxazole,substituted or unsubstituted oxadiazole, substituted or unsubstitutedisoxazole, substituted or unsubstituted thiophene, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted thiadiazole, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrazine, substituted orunsubstituted pyrimidine, substituted or unsubstituted pyridazine,substituted or unsubstituted triazine, substituted or unsubstitutedtetrazine, or substituted or unsubstituted benzene),

(2-3)

D³ and D⁴ are combined to represent a sulfur atom; D² representsC—R^(C′″) (wherein R^(C′″) has the same meaning as R^(A) describedabove); and D¹ represents a nitrogen atom, or D¹ and D² representC—R^(C″″) (wherein R^(C″″) has the same meaning as R^(C″) describedabove), or

(2-4)

D¹, D², D³ and D⁴ represent C—R^(D) (wherein in R^(D)s, optional twoR^(D)s' adjoining carbon atoms of which are adjacent, together with thetwo adjoining carbon atoms, represent substituted or unsubstitutedalicyclic alkene, substituted or unsubstituted pyrrole, substituted orunsubstituted pyrazole, substituted or unsubstituted furan, substitutedor unsubstituted thiophene, substituted or unsubstituted oxadiazole,substituted or unsubstituted isoxazole, substituted or unsubstitutedisothiazole, substituted or unsubstituted thiadiazole, substituted orunsubstituted pyridine, substituted or unsubstituted pyrazine,substituted or unsubstituted pyrimidine, substituted or unsubstitutedpyridazine, substituted or unsubstituted triazine, or substituted orunsubstituted tetrazine, and each of the remaining R^(D)S independentlyrepresents the same meaning as R^(A) described above), or apharmaceutically acceptable salt thereof.

Hereinafter, the compound represented by formula (I) is called compound(I). Compounds represented by other formula numbers are also called inthe same manner.

In the definition of each group of formula (I), examples of the alkylgroup include straight or branched alkyl groups having from 1 to 16carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,octyl, nonyl, decyl, undecyl, dodecyl, hexadecyl, and the like; examplesof the alicyclic alkyl group include monocyclic groups having from 3 to12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl and cyclododecyl and polycyclicgroups including pinanyl, 1,7,7-trimethylbicyclo[2.2.1]heptyl,adamantyl, hexahydro-4,7-methano-1H-indenyl, 4-hexylbicyclo[2.2.2]octyl,and the like; examples of the alicyclic heterocyclic group includetetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidyl,piperazinyl, morpholinyl, thiomorpholinyl, and the like; examples of thenitrogen-containing heterocyclic group include pyrrolidinyl, piperidino,piperidinyl, homopiperidino, homopiperidinyl, piperazinyl,homopiperazinyl, morpholino, morpholinyl, thiomorpholino,thiomorpholinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,indolyl, indazolyl, benzimidazolyl, benzotriazolyl, and the like;examples of the alkenyl group include straight or branched alkenylgroups having from 2 to 16 carbon atoms, such as vinyl, allyl,1-propenyl, isopropenyl, methacryl, butenyl, crotyl, pentenyl, hexenyl,heptenyl, decenyl, dodecenyl, hexadecenyl, and the like; examples of thealkynyl group include straight or branched alkynyl groups having from 2to 16 carbon atoms, such as ethynyl, propargyl, butynyl, pentynyl,hexynyl, heptynyl, decynyl, dodecynyl, hexadecynyl, and the like;examples of the aryl group include phenyl, naphthyl, anthryl, pyrenyl,and the like; examples of the aralkyl group include those having from 7to 15 carbon atoms, such as benzyl, phenethyl, phenylpropyl,phenylbutyl, benzhydryl, trityl, naphthylmethyl, naphthylethyl, and thelike; and examples of the heteroaryl group include pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl,phthalazinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, thienyl, furyl,pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,thiazolyl, thiadiazolyl, benzothienyl, benzofuryl, indolyl, indazolyl,benzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, purinyl,and the like. The heteroaryl moiety of the heteroarylalkyl group has thesame meaning as the heteroaryl group described above, and its alkylmoiety has the same meaning as the alkyl group described above. Examplesof the alicyclic alkene include those having from 4 to 12 carbon atoms,such as cyclobutene, cyclopentene, cyclohexene, cycloheptene,cyclooctene, cyclododecene, and the like. The halogen atom means anyatom of fluorine, chlorine, bromine and iodine.

The substituents of the substituted alkyl group, substituted alkenylgroup, substituted alkynyl group, substituted alicyclic alkyl group,substituted alicyclic heterocyclic group and substituted alicyclicalkene are the same or different and includes 1 to 3 substituents, suchas a nitro group, a cyano group, a hydroxyl group, an oxo group, ahalogen atom, an alicyclic alkyl group, an aryl group, an alicyclicheterocyclic group, a carboxyl group, a formyl group, G¹—J¹—R¹⁵ {whereinG¹ represents a single bond, an oxygen atom, or a sulfur atom; J¹represents CO, CS, or SO₂; and R¹⁵ represents an alkyl group, analicyclic alkyl group, an alicyclic heterocyclic group, an alkenylgroup, an alkynyl group, an R¹⁶-substituted aryl group (wherein R¹⁶represents an alkyl group, a nitro group, a cyano group, a hydroxylgroup, a halogen atom, or NR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸ are the same ordifferent, and each represents a hydrogen atom, an alkyl group, analicyclic alkyl group, an alicyclic heterocyclic group, an alkenylgroup, an alkynyl group, an aryl group, an aralkyl group, a heteroarylgroup, or a heteroarylalkyl group, or R¹⁷ and R¹⁸ are combined torepresent a nitrogen-containing heterocyclic group)) or an unsubstitutedaryl group, an aralkyl group, a heteroaryl group, a heteroarylalkylgroup, an alkoxy group, a trifluoromethyl group, a trifluoromethoxygroup, an alicyclic alkoxy group, an O-alicyclic hetero ring-substitutedhydroxyl group, an alkenyloxy group, an alkynyloxy group, anR¹⁶-substituted aryloxy group (wherein R¹⁶ has the same meaning asdefined above) or an unsubstituted aryloxy group, an aralkyloxy group, aheteroaryloxy group, a heteroarylalkoxy group, an amino group, analkylamino group, an alicyclic alkylamino group, an R¹⁹-substitutedN-alicyclic hetero ring-substituted amino group (wherein R¹⁹ representsa hydroxyl group, an oxo group, or NR²⁰R²¹ (wherein R²⁰ and R²¹ are thesame or different, and each represents a hydrogen atom, an alkyl group,an alicyclic alkyl group, an alicyclic heterocyclic group, an alkenylgroup, an alkynyl group, an aryl group, an aralkyl group, a heteroarylgroup, or a heteroarylalkyl group, or R²⁰ and R²¹ are combined torepresent a nitrogen-containing heterocyclic group)) or an unsubstitutedN-alicyclic hetero ring-substituted amino group, an alkenylamino group,an alkynylamino group, an R¹⁶-substituted arylamino group (wherein R¹⁶has the same meaning as defined above) or an unsubstituted arylaminogroup, an aralkylamino group, a heteroarylamino group, or aheteroarylalkylamino group}, NR²²R²³ (wherein R²² and R²³ are the sameor different, and each represents a hydrogen atom, an alkyl group, analicyclic alkyl group, an alicyclic heterocyclic group, an alkenylgroup, an alkynyl group, an R¹⁶-substituted aryl group (wherein R¹⁶ hasthe same meaning as defined above) or an unsubstituted aryl group, anaralkyl group, a heteroaryl group, a heteroarylalkyl group, an alkanoylgroup, an alicyclic alkanoyl group, an alicyclic heteroring-carbonylgroup, an alkenoyl group, an alkynoyl group, an R¹⁶-substituted aroylgroup (wherein R¹⁶ has the same meaning as defined above) or anunsubstituted aroyl group, an aralkylcarbonyl group, aheteroarylcarbonyl group, a heteroarylalkylcarbonyl group, analkoxycarbonyl group, an alicyclic alkoxycarbonyl group, an O-alicyclichetero ring-substituted hydroxycarbonyl group, an alkenyloxycarbonylgroup, an alkynyloxycarbonyl group, an R¹⁶-substituted aryloxycarbonylgroup (wherein R¹⁶ has the same meaning as defined above) or anunsubstituted aryloxycarbonyl group, an aralkyloxycarbonyl group, aheteroaryloxycarbonyl group, a heteroarylalkoxycarbonyl group, analkylsulfonyl group, an alicyclic alkylsulfonyl group, an alicyclicheteroring-sulfonyl group, an alkenylsulfonyl group, an alkynylsulfonylgroup, an R¹⁶-substituted arylsulfonyl group (wherein R¹⁶ has the samemeaning as defined above) or an unsubstituted arylsulfonyl group, anaralkylsulfonyl group, a heteroarylsulfonyl group, aheteroarylalkylsulfonyl group, or —CQ^(F)NR^(17A)R^(18A) (wherein Q^(F)represents an oxygen atom or a sulfur atom; and R^(17A) and R^(18A) havethe same meanings as R¹⁷ and R¹⁸ defined above), or R²² and R²³ are combnitrogen-containing heterocyclic group), an alkoxy group, an alicyclicalkoxy group, an O-alicyclic hetero ring-substituted hydroxyl group, analkenyloxy group, an alkynyloxy group, an R¹⁶-substituted aryloxy group(wherein R¹⁶ has the same meaning as defined above) or an unsubstitutedaryloxy group, an aralkyloxy group, a heteroaryloxy group, aheteroarylalkoxy group, a sulfo group, a trifluoromethylthio group, analkylthio group, an alicyclic alkylthio group, an alicyclicheteroring-thio group, an alkenylthio group, an alkynylthio group, anR¹⁶-substituted arylthio group (wherein R¹⁶ has the same meaning asdefined above) or an unsubstituted arylthio group, an aralkylthio group,a heteroarylthio group, a heteroarylalkylthio group, atrifluoromethylsulfinyl group, an alkylsulfinyl group, an alicyclicalkylsulfinyl group, an alicyclic heteroring-sulfinyl group, analkenylsulfinyl group, an alkynylsulfinyl group, an R¹⁶-substitutedarylsulfinyl group (wherein R¹⁶ has the same meaning as defined above)or an unsubstituted arylsulfinyl group, an aralkylsulfinyl group, aheteroarylsulfinyl group, a heteroarylalkylsulfinyl group, and the like.

The substituents of the substituted nitrogen-containing heterocyclicgroup, substituted aryl group, substituted aralkyl group, substitutedheteroaryl group, substituted heteroarylalkyl group, substitutedpyrrole, substituted pyrazole, substituted imidazole, substitutedimidazol-2-one, substituted imidazole-2-thione, substituted triazole,substituted furan, substituted 1,3-dioxole, substituted 1,4-dioxene,substituted thiophene, substituted oxazole, substituted oxadiazole,substituted isoxazole, substituted thiazole, substituted isothiazole,substituted thiadiazole, substituted pyridine, substituted pyrazine,substituted pyrimidine, substituted pyridazine, substituted triazine,substituted tetrazine and substituted phenyl are the same or different,and includes 1 to 3 substituents, such as a nitro group, a cyano group,a hydroxyl group, a halogen atom, a methylenedioxy group, (OCH₂CH₂)_(n)O(wherein n is an integer of 1 to 6), a trimethylene group, atrifluoromethyl group, a difluoromethoxy group, a trifluoromethoxygroup, an azido group, a thiocyanato group, an R¹⁹-substituted alkylgroup (wherein R¹⁹ has the same meaning as defined above) or anunsubstituted alkyl group, an R¹⁶-substituted alicyclic alkyl group(wherein R¹⁶ has the same meaning as defined above) or an unsubstitutedalicyclic alkyl group, an alicyclic heterocyclic group, an alkenylgroup, an alkynyl group, an aryl group, an aralkyl group, a heteroarylgroup, a heteroarylalkyl group, a carboxyl group, a formyl group,G¹—J¹—R¹⁵ (wherein G¹, J¹ and R¹⁵ have the same meanings as definedabove), NR²²R²³ (wherein R²² and R²³ have the same meanings as definedabove), an alkoxy group, an alicyclic alkoxy group, an O-alicyclichetero ring-substituted hydroxyl group, an alkenyloxy group, analkynyloxy group, an R¹⁶-substituted aryloxy group (wherein R¹⁶ has thesame meaning as defined above) or an unsubstituted aryloxy group, anaralkyloxy group, a heteroaryloxy group, a heteroarylalkoxy group, asulfo group, a trifluoromethylthio group, an alkylthio group, analicyclic alkylthio group, an alicyclic-heteroring-thio group, analkenylthio group, an alkynylthio group, an R¹⁶-substituted arylthiogroup (wherein R¹⁶ has the same meaning as defined above) or anunsubstituted arylthio group, an aralkylthio group, a heteroarylthiogroup, a heteroarylalkylthio group, a trifluoromethylsulfinyl group, analkylsulfinyl group, an alicyclic alkylsulfinyl group, an alicyclicheteroring-sulfinyl group, an alkenylsulfinyl group, an alkynylsulfinylgroup, an R¹⁶-substituted arylsulfinyl group (wherein R¹⁶ has the samemeaning as defined above) or an unsubstituted arylsulfinyl group, anaralkylsulfinyl group, a heteroarylsulfinyl group, aheteroarylalkylsulfinyl group, an R¹⁶-substituted arylazo group (whereinR¹⁶ has the same meaning as defined above) or an unsubstituted arylazogroup, a heteroarylazo group, and the like.

In the above definition of each substituent, the alkyl moiety of thealkoxy group, alkylamino group, alkanoyl group, alkoxycarbonyl group,alkylthio group and alkylsulfinyl group has the same meaning as thealkyl group described above; the alicyclic alkyl moiety of the alicyclicalkoxy group, alicyclic alkylamino group, alicyclic alkanoyl group,alicyclic alkoxycarbonyl group, alicyclic alkylsulfonyl group, alicyclicalkylthio group and alicyclic alkylsulfinyl group has the same meaningas the alicyclic alkyl group described above; the alicyclic hetero ringmoiety of the O-alicyclic hetero ring-substituted hydroxyl group,N-alicyclic hetero ring-substituted amino group, alicyclicheteroring-carbonyl group, O-alicyclic hetero ring-substitutedhydroxycarbonyl group, alicyclic heteroring-sulfonyl group, alicyclicheteroring-thio group and alicyclic heteroring-sulfinyl group has thesame meaning as the alicyclic heterocyclic group described above; thealkenyl moiety of the alkenyloxy group, alkenylamino group, alkenoylgroup, alkenyloxycarbonyl group, alkenylsulfonyl group, alkenylthiogroup and alkenylsulfinyl group has the same meaning as the alkenylgroup described above; the alkynyl moiety of the alkynyloxy group,alkynylamino group, alkynoyl group, alkynylsulfonyl group, alkynylthiogroup and alkynylsulfinyl group has the same meaning as the, alkynylgroup described above; the aryl moiety of the aryloxy group, arylaminogroup, aroyl group, aryloxycarbonyl group, arylsulfonyl group, arylthiogroup, arylsulfinyl group and arylazo group has the same meaning as thearyl group described above; the aralkyl moiety of the aralkyloxy group,aralkylamino group, aralkylcarbonyl group, aralkyloxycarbonyl group,aralkylsulfonyl group, aralkylthio group and aralkylsulfinyl group hasthe same meaning as the aralkyl group described above; the heteroarylmoiety of the heteroaryloxy group, heteroarylamino group,heteroarylcarbonyl group, heteroaryloxycarbonyl group,heteroarylsulfonyl group, heteroarylthio group, heteroarylsulfinyl groupand heteroarylazo group has the same meaning as the heteroaryl groupdescribed above; and the heteroarylalkyl moiety of heteroarylalkoxygroup, heteroarylalkylamino group, heteroarylalkylcarbonyl group,heteroarylalkoxycarbonyl group, heteroarylalkylsulfonyl group,heteroarylalkylthio group and heteroarylalkylsulfinyl group has the samemeaning as the heteroarylalkyl group described above. Also, thealicyclic alkyl group, aryl group, alicyclic heterocyclic group, alkylgroup, alkenyl group, alkynyl group, halogen atom, aralkyl group,heteroaryl group, heteroarylalkyl group and nitrogen-containingheterocyclic group have the same meanings as described above,respectively.

As preferred embodiments of the present invention, nitrogen-containingheterocyclic compounds wherein W represents 1,4-piperazinediyl orpharmaceutically acceptable salts thereof can be exemplified.Particularly, compounds wherein at least one of X and Z represents anitrogen atom, and Y represents C—R^(A) (wherein R^(A) has the samemeaning as defined above) are preferred, and compounds wherein X and Zrepresent nitrogen atoms, and R^(A) represents a hydrogen atom or NR⁹R¹⁰(wherein R⁹ and R¹⁰ have the same meanings as defined above) arepreferred. Further, nitrogen-containing heterocyclic compounds wherein Uis NR¹R² (wherein R¹ and R² have the same meanings as defined above) orpharmaceutically acceptable salts thereof are preferred.

Among these nitrogen-containing heterocyclic compounds orpharmaceutically acceptable salts thereof, in preferred compounds, R¹represents a hydrogen atom; and R² represents a hydrogen atom, asubstituted alkyl group, a substituted or unsubstituted alicyclic alkylgroup, a substituted or unsubstituted alicyclic heterocyclic group, asubstituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a substituted or unsubstituted aryl group,a substituted or unsubstituted aralkyl group, a substituted orunsubstituted heteroaryl group, or a substituted or unsubstitutedheteroarylalkyl group, and more preferably, R² represents a substitutedor unsubstituted aryl group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted heteroaryl group, or a substitutedor unsubstituted heteroarylalkyl group.

In addition, the following nitrogen-containing heterocyclic compounds orpharmaceutically acceptable salts thereof are excellent among the abovepreferred embodiments.

Preferred examples include nitrogen-containing heterocyclic compounds orpharmaceutically acceptable salts thereof, wherein V represents N—R⁶(wherein R⁶ has the same meaning as defined above); and

1) D¹ and D² are combined to represent N—R^(2A) (wherein R^(2A) has thesame meaning as defined above); and D³ and D⁴ each independentlyrepresents C—R^(B′) (wherein R^(B′) has the same meaning as definedabove),

2) D¹ and D² each independently represents C—R^(B′) (wherein R^(B′) hasthe same meaning as defined above); and D³ and D⁴ are combined torepresent N—R^(2A) (wherein R^(2A) has the same meaning as definedabove),

3) D¹ and D⁴ each independently represents C—R^(B′) (wherein R^(B′) hasthe same meaning as defined above); and D² and D³ are combined torepresent N—R^(2A) (wherein R^(2A) has the same meaning as definedabove),

4) D¹ represents C—R^(B′) (wherein R^(B′) has the same meaning asdefined above); D² and D³ are combined to represent a nitrogen atom; andD⁴ represents N—R^(2A′) (wherein R^(2A′) has the same meaning as definedabove),

5) D⁴ represents C—R^(B′) (wherein R^(B′) has the same meaning asdefined above); D² and D³ are combined to represent a nitrogen atom; andD¹ represents N—R^(2A′) (wherein R^(2A′) has the same meaning as definedabove),

6) D¹ and D² are combined to represent N—R^(2A) (wherein R^(2A) has thesame meaning as defined above); D³ represents C—R^(B′) (wherein R^(B′)has the same meaning as defined above); and D⁴ represents a nitrogenatom,

7) D¹ and D² are combined to represent a nitrogen atom; D³ representsC—R^(B′) (wherein R^(B′) has the same meaning as defined above); and D⁴represents N—R^(2A′) (wherein R^(2A′) has the same meaning as definedabove),

8) D¹, D² and D³ each independently represents C—R^(B) (Wherein R^(B)has the same meaning as defined above); and D⁴ represents a nitrogenatom,

9) D¹, D² and D⁴ each independently represents C—R^(B) (wherein R^(B)has the same meaning as defined above); and D³ represents a nitrogenatom,

10) D¹, D³ and D⁴ each independently represents C—R^(B) (wherein R^(B)has the same meaning as defined above); and D² represents a nitrogenatom,

11) D², D³ and D⁴ each independently represents C—R^(B) (wherein R^(B)has the same meaning as defined above); and D¹ represents a nitrogenatom,

12) D¹ and D³ represent nitrogen atoms; and D² and D⁴ each independentlyrepresents C—R^(B) (wherein R^(B) has the same meaning as definedabove),

13) D¹ and D³ each independently represents C—R^(B) (wherein R^(B) hasthe same meaning as defined above); and D² and D⁴ represent nitrogenatoms,

14) D¹ and D² each independently represents C—R^(B) (wherein R^(B) hasthe same meaning as defined above); and D³ and D⁴ represent nitrogenatoms,

15) D¹ and D⁴ each independently represents C—R^(B) (wherein R^(B) hasthe same meaning as defined above); and D² and D³ represent nitrogenatoms,

16) D³ and D⁴ each independently represent C—R^(B) (wherein R^(B) hasthe same meaning as defined above); and D¹ and D² represent nitrogenatoms,

17) D² and D³ each independently represents C—R^(B) (wherein R^(B) hasthe same meaning as defined above); and D¹ and D⁴ represent nitrogenatoms,

18) D¹, D², D³ and D⁴ each independently represents C—R^(B) (whereinR^(B) has the same meaning as defined above),

19) D¹ and D² each independently represents C—R^(B′) (wherein R^(B′) hasthe same meaning as defined above); and D³ and D⁴ are combined torepresent a sulfur atom,

20) D¹ and D⁴ each independently represents C—R^(B′) (wherein R^(B′) hasthe same meaning as defined above); and D² and D³ are combined torepresent a sulfur atom, or

21) D³ and D⁴ each independently represents C—R^(B′)(wherein R^(B′) hasthe same meaning as defined above); and D¹ and D² are combined torepresent a sulfur atom.

Also, preferred examples include nitrogen-containing heterocycliccompounds or pharmaceutically acceptable salts thereof, wherein Vrepresents an oxygen atom or a sulfur atom; and

1) D¹ and D² are combined to represent N—R^(2B) (wherein R^(2B) has thesame meaning as defined above); and D³ and D⁴ each independentlyrepresents C—R^(C) (wherein R_(C) has the same meaning as definedabove),

2) D¹ and D² each independently represents C—R^(C) (wherein R^(C) hasthe same meaning as defined above); and D³ and D⁴ are combined torepresent N—R^(2B) (wherein R^(2B) has the same meaning as definedabove),

3) D¹ and D⁴ each independently represents C—R^(C) (wherein R^(C) hasthe same meaning as defined above); and D² and D³ are combined torepresent N—R^(2B) (wherein R^(2B) has the same meaning as definedabove),

4) D¹ represents C—R^(C) (wherein R^(C) has the same meaning as definedabove); D² and D³ are combined to represent a nitrogen atom; and D⁴represents N—R^(2B′) (wherein R^(2B′) has the same meaning as definedabove),

5) D⁴ represents C—R^(C) (wherein R^(C) has the same meaning as definedabove); D² and D³ are combined to represent a nitrogen atom; and D¹represents N—R^(2B′)′(wherein R^(2B′) has the same meaning as definedabove),

6) D¹ and D² are combined to represent N—R^(2B) (wherein R^(2B) has thesame meaning as defined above); D³ represents C—R^(C) (wherein R^(C) hasthe same meaning as defined above); and D⁴ represents a nitrogen atom,

7) D¹ and D² are combined to represent a nitrogen atom; D³ representsC—R^(C) (wherein R^(C) has the same meaning as defined above); and D⁴represents N—R^(2B′) (wherein R^(2B′) has the same meaning as definedabove),

8) D¹, D² and D³ each independently represents C—R^(C) (wherein R^(C)has the same meaning as defined above); and D⁴ represents a nitrogenatom,

9) D¹, D² and D⁴ each independently represents C—R^(C) (wherein R^(C)has the same meaning as defined above); and D³ represents a nitrogenatom,

10) D¹, D³ and D⁴ each independently represents C—R^(C) (wherein R^(C)has the same meaning as defined above); and D² represents a nitrogenatom,

11) D², D³ and D⁴ each independently represents C—R^(C) (wherein R^(C)has the same meaning as defined above); and D¹ represents a nitrogenatom,

12) D¹ and D³ represent nitrogen atoms; and D² and D⁴ each independentlyrepresents C—R^(C) (wherein R^(C) has the same meaning as definedabove),

13) D¹ and D³ each independently represents C—R^(C) (wherein R^(C) hasthe same meaning as defined above); and D² and D⁴ are nitrogen atoms,

14) D¹ and D² each independently represents C—R^(C) (wherein R^(C) hasthe same meaning as defined above); and D³ and D⁴ are nitrogen atoms,

15) D¹ and D⁴ each independently represents C—R^(C) (wherein R^(C) hasthe same meaning as defined above); and D² and D³ are nitrogen atoms,

16) D³ and D⁴ each independently represents C—R^(C) (wherein R^(C) hasthe same meaning as defined above); and D¹ and D² are nitrogen atoms,

17) D² and D³ each independently represents C—R^(C) (wherein R^(C) hasthe same meaning as defined above); and D¹ and D⁴ are nitrogen atoms,

18) D¹, D², D³ and D⁴ each independently represents C—R^(D) (whereinR^(D) has the same meaning as defined above),

19) D¹ and D² each independently represents C—R^(C″″) (wherein R^(C″″)has the same meaning as defined above); and D³ and D⁴ are combined torepresent a sulfur atom,

20) D¹ and D⁴ each independently represents C—R^(C) (wherein R^(C) hasthe same meaning as defined above); and D² and D³ are combined torepresent a sulfur atom, or

21) D³ and D⁴ each independently represents C—R^(C″) (wherein R^(C″) hasthe same meaning as defined above); and D¹ and D² are combined torepresent a sulfur atom.

Also, preferred examples include nitrogen-containing heterocycliccompound or pharmaceutically acceptable salts thereof, wherein Vrepresents N—CN; and

1) D¹ and D² are combined to represent a nitrogen atom; D³ representsC—R^(B′) (wherein R^(B′) has the same meaning as defined above); and D⁴represents N—R^(2A′) (wherein R^(2A′) has the same meaning as definedabove),

2) D¹, D² and D⁴ each independently represents C—R^(B) (wherein R^(B)has the same meaning as defined above); and D³ represents a nitrogenatom, or

3) D¹, D², D³ and D⁴ each independently represents C—R^(B) (whereinR^(B) has the same meaning as defined above).

Also, preferred examples include nitrogen-containing heterocycliccompounds or pharmaceutically acceptable salts thereof, wherein Vrepresents N—CN; and

D¹ and D² each independently represents C—R^(B′) (wherein R^(B′) has thesame meaning as defined above); and D³ and D⁴ are combined to representN—R^(2A) (wherein R^(2A) has the same meaning as defined above).

Also, preferred examples include nitrogen-containing heterocycliccompounds or pharmaceutically acceptable salts thereof, wherein Vrepresents N—CN; and

1) D¹, D² and D³ each independently represents C—R^(B) (wherein R^(B)has the same meaning as defined above); and D⁴ represents a nitrogenatom,

2) D¹, D² and D⁴ each independently represents C—R^(B) (wherein R^(B)has the same meaning as defined above); and D³ represents a nitrogenatom,

3) D¹, D³ and D⁴ each independently represents C—R^(B) (wherein R^(B)has the same meaning as defined above); and D² represents a nitrogenatom, or

4) D², D³ and D⁴ each independently represents C—R^(B) (wherein R^(B)has the same meaning as defined above); and D¹ represents a nitrogenatom.

Also, preferred examples include nitrogen-containing heterocycliccompounds or pharmaceutically acceptable salts thereof, wherein Vrepresents N—CN; and

1) D¹ and D³ represent nitrogen atoms; and D² and D⁴ each independentlyrepresents C—R^(B) (wherein R^(B) has the same meaning as definedabove), or

2) D¹ and D³ each independently represents C—R^(B) (wherein R^(B) hasthe same meaning as defined above); and D² and D⁴ represent nitrogenatoms.

Also, preferred examples include nitrogen-containing heterocycliccompounds or pharmaceutically acceptable salts thereof, wherein Vrepresents an oxygen atom or a sulfur atom; and

1) D¹ and D² are combined to represent a nitrogen atom; D³ representsC—R^(C) (wherein R^(C) has the same meaning as defined above); and D⁴represents N—R^(2B′) (wherein R^(2B′) has the same meaning as definedabove),

2) D¹, D² and D⁴ each independently represents C—R^(C) (wherein R^(C)has the same-meaning as defined above); and D³ represents a nitrogenatom, or

3) D¹, D², D³ and D⁴ each independently represents C—R^(D) (whereinR^(D) has the same meaning as defined above).

Also, preferred examples include nitrogen-containing heterocycliccompounds or pharmaceutically acceptable salts thereof, wherein Vrepresents an oxygen atom or a sulfur atom; and

D¹ and D² each independently represents C—R^(B′) (wherein R^(B′) has thesame meaning as defined above); and D³ and D⁴ are combined to representN—R^(2A) (wherein R^(2A) has the same meaning as defined above).

Also preferred examples include nitrogen-containing heterocycliccompounds or pharmaceutically acceptable salts thereof, wherein Vrepresents an oxygen atom or a sulfur atom; and

1) D¹, D² and D³ each independently represents C—R^(B) (wherein R^(B)has the same meaning as defined above); and D⁴ represents a nitrogenatom,

2) D¹, D² and D⁴ each independently represents C—R^(B) (wherein R^(B)has the same meaning as defined above); and D³ represents a nitrogenatom,

3) D¹, D³ and D⁴ each independently represents C—R^(B) (wherein R^(B)has the same meaning as defined above); and D² represents a nitrogenatom, or

4) D², D³ and D⁴ each independently represents C—R^(B) (wherein R^(B)has the same meaning as defined above); and D¹ represents a nitrogenatom.

Also, preferred examples include nitrogen-containing heterocycliccompounds or pharmaceutically acceptable salts thereof, wherein Vrepresents an oxygen atom or a sulfur atom; and

1) D¹ and D³ represent nitrogen atoms; and D² and D⁴ each independentlyrepresents C—R^(B) (wherein R^(B) has the same meaning as definedabove), or

2) D¹ and D³ each independently represents C—R^(B) (wherein R^(B) hasthe same meaning as defined above); and D² and D⁴ represent nitrogenatoms.

Also, preferred examples include nitrogen-containing heterocycliccompounds or pharmaceutically acceptable salts thereof, wherein Vrepresents an oxygen atom or a sulfur atom; D¹, D², D³ and D⁴ representC—R^(D) (wherein R^(D) has the same meaning as defined above); andoptional two R^(D)s' adjoining carbon atoms of which are adjacent,together with the two adjoining carbon atoms, represent substituted orunsubstituted pyrrole, substituted or unsubstituted pyrazole,substituted or unsubstituted pyridine, substituted or unsubstitutedpyrimidine, substituted or unsubstituted pyridazine, or substituted orunsubstituted pyrazine.

In order to explain preferred embodiments of the present invention morespecifically, some chemical structures in Compound (I) are exemplifiedbelow. The present invention is characterized by the substituent,W(C=V)U (wherein W, V and U have the same meanings as defined above,respectively) of Compound (I) as a matter of course, and thissubstituent binds to a bicyclic or tricyclic hetero ring represented byD¹, D², D³, D⁴, X, Y, Z and two carbon atoms , which is also acharacteristic of the present invention, at the position shown informula (I). Compounds in which X and Z each represents a nitrogen atomare one of the preferred embodiments, and compounds in whichcorresponding quinazoline or pyrimidine forms a condensed polycyclichetero ring system are exemplified as group names below.

Examples of the group showing a preferred ring structure includepyrrolo[3,2-g]quinazolinyl, pyrazino[2,3-g]quinazolinyl,benzothieno[3,2-d]pyrimidinyl,thiazolo[5′,4′;4,5]thieno[3,2-d]pyrimidinyl,pyrido[2′,3′;4,5]thieno[3,2-d]pyrimidinyl, indolo[3,2-d]pyrimidinyl,indolo[2,3-d]pyrimidinyl, benzofurano[3,2-d]pyrimidinyl,pyrimido[4,5-f]quinazolinyl, benzothieno[2,3-d]pyrimidinyl,thieno[2′,3′;4,5]thieno[3,2-d]pyrimidinyl,thieno[3′,2′;4,5]thieno[2,3-d]pyrimidinyl,imidazo[5′,4′;4,5]thieno[3,2-d]pyrimidinyl,pyrido[3′,2′;4,5]thieno[3,2-d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl,pyrazolo[3,4-d]pyrimidinyl, purinyl, pyrido[2,3-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl,pyrido[3,2-d]pyrimidinyl, pyrimidino[5,4-d]pyrimidinyl,pyrimidino[4,5-d]pyrimidinyl, pyrrolo[3,2-g]quinazolinyl,pyrrolo[2,3-f]quinazolinyl, pyrazolo[4,3-g]quinazolinyl,pyrazolo[3,4-g]quinazolinyl, furo[2,3-d]pyrimidinyl,furo[3,4-d]pyrimidinyl, furo[3,2-d]pyrimidinyl,triazolo[4,5-d]pyrimidinyl, and the like, though preferred ringstructures of the present invention are not limited thereto.

Examples of the pharmaceutically acceptable salt of Compound (I) includepharmaceutically acceptable acid addition salts, metal salts, ammoniumsalts, organic amine addition salts, amino acid addition salts, and thelike. Examples of the pharmaceutically acceptable acid addition salt ofCompound (I) include inorganic acid salts, such as hydrochloride,sulfate, phosphate, and the like, and organic acid salts, such asacetate, maleate, fumarate, tartrate, citrate, methanesulfonate, and thelike; examples of the pharmaceutically acceptable metal salt includealkali metal salts, such as sodium salt, potassium salt, and the like,alkaline earth metal salts, such as magnesium salt, calcium salt, andthe like, aluminum salt, zinc salt, and the like; examples of thepharmaceutically acceptable ammonium salt include salts such asammonium, tetramethylammonium, and the like; examples of thepharmaceutically acceptable organic amine addition salt include additionsalts of morpholine, piperidine, and the like; and examples of thepharmaceutically acceptable amino acid addition salt include additionsalts of lysine, glycine, phenylalanine, and the like.

Next, processes for producing Compound (I) are described.

Production Process 1

Compound (I-a), wherein U represents NHR²; and V represents an oxygenatom or a sulfur atom, can be produced according to the followingreaction step.

(In the formulae, D¹, D², D³, D⁴, R², W, X, Y and Z have the samemeanings as defined above, respectively; V′ represents an oxygen atom ora sulfur atom; and W′ represents 1-piperazinyl or 1-homopiperazinyl inwhich carbons on the ring may be substituted with 1 to 4 alkyl groupswhich are the same or different.)

Compound (I-a) can be obtained by allowing Compound (II) to react withan isocyanate (R²—N═C═O) which is commercially available or can beobtained by a known process [for example, Organic Functional GroupPreparations, S. R. Sandler et al., 1: 305, Academic Press Inc., NewYork and London (1968), Synthetic Organic Chemistry, R. B. Wagner etal., 3rd ed., p. 640, John Wiley (1961), etc.] or with an isothiocyanate(R²—N═C═S) [e.g., Organic Functional Group Preparations, S. R. Sandleret al., 1: 312, Academic Press Inc., New York and London (1968),Synthetic Organic Chemistry, R. B. Wagner et al., 3rd ed., p. 829, JohnWiley (1961), etc.] at a temperature between −20° C. and the boilingpoint of a used solvent for 10 minutes to 48 hours in an appropriateinert solvent, for example, a halogenated hydrocarbon, such aschloroform, dichloromethane, etc., an aromatic hydrocarbon, such asbenzene, toluene, etc., an ether solvent,, such as diethyl ether,tetrahydrofuran (THF), 1,4-dioxane, etc., a lower alcohol, such asmethanol, ethanol, isopropanol, etc., an aprotic polar solvent, such asdimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, pyridine,etc., or a mixed solvent thereof, optionally in the presence of a base,for example, an organic base, such as triethylamine, pyridine, etc., aninorganic base, such as potassium carbonate, sodium. hydroxide, sodiumhydride, etc., a metal alkoxide, such as sodium methoxide, potassiumtert-butoxide, etc., or the like.

Compound (II) as the starting material can be obtained by the processdisclosed in Japanese Published Unexamined Patent Application No.104074/89, South African Patent 67 06512, Ind. J. Chem., 26B: 550-555(1987), or the like, or a modified process thereof, or can also beobtained by a process of the following reaction scheme.

(In the formulae, D¹, D², D³, D⁴, W′, X, Y and Z have the same meaningsas defined above, respectively; and L¹ represents a leaving group.)

Examples of the leaving group in the definition of L¹ include halogenatoms, substituted or unsubstituted alkoxy groups, substituted orunsubstituted aryloxy groups, substituted or unsubstituted alkylthiogroups, substituted or unsubstituted alkylsulfinyl groups, substitutedor unsubstituted alkylsulfonyl groups, substituted or unsubstitutedalkylsulfonyloxy groups, substituted or unsubstituted arylsulfonyloxygroups, and the like. The halogen atom, alkoxy group, aryloxy group,alkylthio group and alkylsulfinyl group have the same meanings asdefined above, respectively, the alkyl moiety of the alkylsulfonyl groupand alkylsulfonyloxy group has the same meaning as the alkyl groupdefined above, and the aryl moiety of the arylsulfonyloxy group has thesame meaning as the aryl defined above. Examples of the substituentinclude halogen atoms, alkyl groups, a nitro group, and the like, andthe halogen atom has the same meaning as the halogen atom defined above.

Compound (II) can be obtained by allowing Compound (III) to react with acompound W′—H at a temperature between room temperature and the boilingpoint of a used solvent for 10 minutes to 48 hours in an appropriateinert solvent, for example, a lower alcohol, such as methanol, ethanol,isopropanol, etc., a halogenated hydrocarbon, such as chloroform,dichloromethane, etc., an aromatic hydrocarbon, such as benzene,toluene, etc., an ether solvent, such as diethyl ether, THF,1,4-dioxane, etc., an aprotic polar solvent, such as dimethylformamide,N-methylpyrrolidone, dimethyl sulfoxide, pyridine, etc., or a mixedsolvent thereof, optionally in the presence of a base. Examples of thebase include organic bases, such as triethylamine, pyridine, etc.,inorganic bases, such as potassium carbonate, sodium hydroxide, sodiumhydride, etc., metal alkoxides, such as sodium methoxide, potassiumtert-butoxide, etc., and the like.

When the group defined in the above production process changes underconditions of the practical process or is inappropriate for carrying outthe process, the objective compound can be obtained by introducing thecompound W′—H, after its protection excluding the reaction point, intoCompound (III) and then carrying out deprotection. Examples of theprotecting group include protecting groups disclosed in ProtectiveGroups in Organic Synthesis, T. W. Green, John Wiley & Sons Inc. (1981)and the like, such as ethoxycarbonyl, tert-butoxycarbonyl, acetyl,benzyl, and the like. Introduction and elimination of the protectinggroup can be carried out by a process commonly used in the syntheticorganic chemistry (e.g., a process disclosed in the above ProtectiveGroups in Organic Synthesis can be referred to).

A commercially available compound can be used as Compound (III) as thestarting material, or Compound (III) as the starting material can beproduced by the process disclosed in WO 95/19970, J. Med. Chem., 38:3780-3788 (1995), J. Med. Chem., 39: 918-928 (1996), J. Med. Chem., 39:1823-1835 (1996), J. Med. Chem., 40: 1519-1529 (1997), J. Med. Chem.,40: 1820-1826 (1997), Bioorg. Med. Chem. Lett., 5: 2879-2884 (1995), J.Chem. Soc., pp. 890-899 (1947), J. Chem. Soc., pp. 561-572 (1962), J.Chem. Soc., B, pp. 449-454 (1967), J. Indian Chem. Soc., 36: 787-791(1959), J. Org. Chem., 17: 1571-1575 (1952), J. Med. Chem., 14:1060-1066 (1971), French Patent 1388756, J. Am. Chem. Soc., 68:1204-1208 (1946), Ind. J. Chem., 26B: 550-555 (1987), Japanese PublishedUnexamined Patent Application No. 120872/85, South African Patent 6706512, or the like, the process described in Reference Examples, or amodified process thereof.

Production Process 2

Compound (I) can be produced according to the following reaction step.

(In the formulae, L² has the same meaning as L¹ described above; and D¹,D², D³, D⁴, U, V, W, W′, X, Y and Z have the same meanings as definedabove, respectively.)

Compound (I) can be produced by allowing Compound (II) to react withCompound (IV) at a temperature between −20° C and the boiling point of aused solvent for 10 minutes to 48 hours in an appropriate inert solvent,for example, a halogenated hydrocarbon, such as chloroform,dichloromethane, etc., an aromatic hydrocarbon, such as benzene,toluene, etc., an ether solvent, such as diethyl ether, THF,1,4-dioxane, etc., a lower alcohol, such as methanol, ethanol,isopropanol, etc., an aprotic polar solvent, such as dimethylformamide,N-methylpyrrolidone, dimethyl sulfoxide, pyridine, etc., or a mixedsolvent thereof, optionally in the presence of a base. Examples of thebase include organic. bases, such as triethylamine, pyridine, etc.,inorganic bases, such as potassium carbonate, sodium hydroxide, sodiumhydride, etc., metal alkoxides, such as sodium methoxide, potassiumtert-butoxide, etc., and the like.

A commercially available product can be used as Compound (IV) as thestarting material, or Compound (IV) as the starting material can beproduced by the process described in Beilstein, 4: 73 (1922), Beilstein,4: 75 (1922), Bioorg. Med. Chem. Lett., 17: 3095-3100 (1997), J. Med.Chem., 38: 3236-3245 (1995), Japanese Published Unexamined PatentApplication No. 18557/78, Jikken Kagaku Koza 20—Yuki Gosei II, 4th ed.,p. 355, The Chemical Society of Japan, Maruzen (Tokyo) (1992), Methodender Organischen Chemie, vol. E11, Organische Schwefel-Verbindungen,Dieter Klamann, p. 263, Georg Thieme Verlag (Stuttgart, New York)(1985), or the like, or a modified process thereof.

Production Process 3

Compound (I) can also be produced according to the following reactionstep.

(In the formulae, L¹, D¹, D², D³, D⁴, U, V, W, W′, X, Y and Z have thesame meanings as defined above, respectively.)

Compound (I) can be produced by allowing Compound (III) to react withCompound (V) at a temperature between room temperature and the boilingpoint of a used solvent for 10 minutes to 48 hours in an appropriateinert solvent, for example, a halogenated hydrocarbon, such aschloroform, dichloromethane, etc., an aromatic hydrocarbon, such asbenzene, toluene, etc., an ether solvent, such as diethyl ether, THF,1,4-dioxane, etc., a lower alcohol, such as methanol, ethanol,isopropanol, etc., an aprotic polar solvent, such as dimethylformamide,N-methylpyrrolidone, dimethyl sulfoxide, pyridine, etc., or a mixedsolvent thereof, optionally in the presence of a base. Examples of thebase include organic bases, such as triethylamine, pyridine, etc.,inorganic bases, such as potassium carbonate, sodium hydroxide, sodiumhydride, etc., metal alkoxides, such as sodium methoxide, potassiumtert-butoxide, etc., and the like.

Compound (V) as the starting material can be produced by the processdisclosed in Examples or Reference Examples or a modified processthereof.

Production Process 4

Compound (I) can also be produced according to the following reactionstep.

(In the formulae, L³ has the same meaning as L¹ described above; and D¹,D², D³, D⁴, U, V, W, X, Y and Z have the same meanings as defined above,respectively.)

Compound (I) can be produced by allowing Compound (VI) to react with acompound U-H at a temperature between room temperature and the boilingpoint of a used solvent for 10 minutes to 48 hours in an appropriateinert solvent, for example, a halogenated hydrocarbon, such aschloroform, dichloromethane, etc., an aromatic hydrocarbon, such asbenzene, toluene, etc., an ether solvent, such as diethyl ether, THF,1,4-dioxane, etc., a lower alcohol, such as methanol, ethanol,isopropanol, etc., an aprotic polar solvent, such as dimethylformamide,N-methylpyrrolidone, dimethyl sulfoxide, pyridine, etc., or a mixedsolvent thereof, optionally in the presence of a base. Examples of thebase include organic bases, such as triethylamine, pyridine, etc.,inorganic bases, such as potassium carbonate, sodium hydroxide, sodiumhydride, etc., metal alkoxides, such as sodium methoxide, potassiumtert-butoxide, etc., and the like.

Compound (VI) as the starting material can be produced by the processdisclosed in South African Patent 67 06512, U.S. Pat. No. 3,723,434,Japanese Published Unexamined Patent Application No. 18557/78, or thelike, or a modified process thereof.

Production Process 5

Compound (I-b), wherein U represents NHR²; and V represents N—R⁶, canalso be produced according to the following reaction step.

(In the formulae, L⁴ has the same meaning as L¹ defined above; and D¹,D², D³, D⁴, R², R⁶, W, X, Y and Z have the same meanings as definedabove, respectively.)

Compound (I-b) can be produced by allowing Compound (VII) to react witha compound R⁶—NH₂ at a temperature between room temperature and theboiling point of a used solvent for 10 minutes to 48 hours in anappropriate inert solvent, for example, a halogenated hydrocarbon, suchas chloroform, dichloromethane, etc., an aromatic hydrocarbon, such asbenzene, toluene, etc., an ether solvent, such as diethyl ether, THF,1,4-dioxane, etc., a lower alcohol, such as methanol, ethanol,isopropanol, etc., an aprotic polar solvent, such as pyridine,dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc., or amixed solvent thereof; optionally in the presence of a base. Examples ofthe base include organic bases, such as triethylamine, pyridine, etc.,inorganic bases, such as potassium carbonate, sodium hydroxide, sodiumhydride, etc., metal alkoxides, such as sodium methoxide, potassiumtert-butoxide, etc., and the like.

Compound (VII) as the starting material can be obtained by the processdisclosed in Japanese Published Unexamined Patent Application No.19671/77, Organic Functional Group Preparations, S. R. Sandler et al.,2: 166-185, Academic Press Inc., New York and London (1971), or thelike, or a modified process thereof.

Production Process 6

Compound (I-c), wherein U represents NR¹R²; and V represents N—CN, canalso be produced according to the following reaction step.

(In the formulae, D¹, D², D³, D⁴, R¹, R², V′, W, X, Y and Z have thesame meanings as defined above, respectively.)

Compound (I-c) can be produced by allowing Compound (I-d) to react withcyanamide at a temperature between room temperature and the boilingpoint of a used solvent for 10 minutes to 48 hours in an appropriateinert solvent, for example, a halogenated hydrocarbon, such aschloroform, dichloromethane, etc., an aromatic hydrocarbon, such asbenzene, toluene, etc., an ether solvent, such as diethyl ether, THF,1,4-dioxane, etc., a lower alcohol, such as methanol, ethanol,isopropanol, etc., an aprotic polar solvent, such as pyridine,dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, pyridine,acetonitrile, etc., or a mixed solvent thereof, in the presence of anappropriate condensing agent, such as 1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or the like, andoptionally in the presence of a base. Examples of the base includeorganic bases, such as triethylamine, pyridine, etc., inorganic bases,such as potassium carbonate, sodium hydroxide, sodium hydride, etc.,metal alkoxides, such as sodium methoxide, potassium tert-butoxide,etc., and the like.

Furthermore, Compound (I-b) can also be obtained by allowing Compound(II) to react with various carbodiimide compounds under conditionssimilar to those in Production Process 1. In addition to thecommercially available product, the carbodiimide used in the reactioncan be produced by the process disclosed in Shin-Jikken Kagaku Koza14—Yukikagobutu no Gosei to Hanno (III), The Chemical Society of Japan,pp. 1644-1652, Maruzen (Tokyo) (1978), Synthetic Communications, 25:43-47 (1995), or the like, or a modified process thereof.

When the group defined in each of the above production processes changesunder conditions of the practical process or is inappropriate forcarrying out the process, the objective compound can be produced byusing protecting group introduction and elimination processes commonlyused in the synthetic organic chemistry [e.g., see Protective Groups inOrganic Synthesis, T. W. Greene, John Wiley & Sons Inc. (1981)].Furthermore, a conversion of the functional group contained in eachsubstituent can also be carried out by a commonly known process [e.g.,Comprehensive Organic Transformations, R. C. Larock (1989), etc.] inaddition to the production processes described above, and novel Compound(I) can also be derived by using some of Compounds (I) as a syntheticintermediate.

The intermediate and the objective compound in each of the aboveproduction processes can be isolated and purified by subjecting them topurification processes ordinary used in the synthetic organic chemistry,such as neutralization, filtration, extraction, washing, drying,concentration, recrystallization, various chromatography, and the like.Furthermore, the intermediates can also be used in the subsequentreaction without carrying out particular purification.

Regio isomers, geometrical isomers, optical isomers or tautomers may bepresent for some of Compounds (I), and all possible isomers includingthem and mixtures thereof are included in the scope of the presentinvention.

In production of a salt of Compound, (I), when Compound (I) is producedin a salt form, it can be purified as such, and when it is produced inits free form, its salt can be formed in the usual way by dissolving orsuspending it in an appropriate organic solvent and adding thereto anacid or a base.

In addition, Compound (I) or a pharmaceutically acceptable salt thereofmay be present in the form of addition products with water or varioussolvents, and these addition products are also included in the scope ofthe present invention.

Examples of Compound (I) obtained by the above production processes areshown in Table 1.

TABLE 1-1

Compound No. V R^(A) R² 1 O H

2 O H

3 S H

4 S H

5 O NH₂

6 O NH₂

7 S NH₂

8 S NH₂

TABLE 1-2

Compound No. V R^(2B′) R²  9 O CH₃

10 O

11 S

TABLE 1-3

Compound No. V R² 12 O

TABLE 1-4

Com- pound No. V R^(2B′) R² 13 O CH₃

14 S CH₃

15 S CH₃

16 O

17 S

TABLE 1-5

Compound No. V R² 18 O

19 S

TABLE 1-6

Compound No. V R² 20 O

21 S

TABLE 1-7

Compound No. Z R^(A) R^(C) 22 N H F 23 CH NH₂ H

TABLE 1-8

Compound No. V R² 24 O

25 O

26 S

27 S

TABLE 1-9

Compound No. R^(E) 28 H 29 2-Cl 30 3-Cl 31 4-Cl 32 4-F 33 4-Br 34 4-CH₃35 4-CH(CH₃)₂ 36 4-OCH₃ 37 4-SCH₃ 38 4-SO₂CH₃

TABLE 1-10

Compound No. R² 39 —(CH₂)₃CH₃ 40

41

42

TABLE 1-11

Compound No. R² 43

44

45

46

47

48

49

TABLE 1-12

Compound No. R² 50

51

52

53

54

55

56

57

TABLE 1-13

Com- pound No. V U 58 CH(NO₂) SCH₃ 59 CH(NO₂)

60 CH(NO₂)

61

62

SCH₃ 63

64 C(CN)₂ SCH₃

TABLE 1-14

Compound No. V U 65 NCN SCH₃ 66 NCN OCH₂CH₃ 67 NCN

68 NCN

TABLE 1-15

Compound No. A 69

70

Next, the pharmacological activity of the compounds of the presentinvention are specifically explained by test examples.

Test Example 1

PDGF Receptor Phosphorylation Inhibition Test

This test was carried out according to the process disclosed in aliterature [J. Biol. Chem., 266: 413-418 (1991)]. In this case, Chinesehamster ovary (CHO) cells to which human β-PDGF receptor cDNA had beeninserted and in which it had been expressed were used in the test. Thetest results were represented by a concentration at which the testcompound inhibits 50% of the PDGF receptor phosphorylation (IC₅₀).

The results are shown in Table 2.

TABLE 2 PDGF receptor phosphorylation inhibition IC₅₀ (μM) Compound 10.29 Compound 3 0.89 Compound 5 0.20 Compound 31 0.38 Compound 41 0.19

Test results on Compounds 22, 50, 52, 63 and 66 were represented by aratio (%) of inhibiting phosphorylation of the PDGF receptor at 10 μM,with the results shown in Table 3.

TABLE 3 PDGF receptor phosphorylation inhibition (%) Compound 22 66Compound 51 82 Compound 53 87 Compound 64 82 Compound 67 95

Although Compound, (I) or a pharmaceutically acceptable salt thereof canbe administered directly as such, generally, it is preferred to provideit in various forms of pharmaceutical preparations. Further, suchpharmaceutical preparations are used for animals and humans.

As their route of administration, it is preferred to use the mosteffective way in carrying out the treatment, and examples include oraladministration and parenteral administration, such as rectal, buccal,subcutaneous, intramuscular, intravenous, and the like.

Examples of the dosage form include capsules, tablets, granules,powders, syrups, emulsions, suppositories, injections, and the like.

Liquid preparations suitable for oral administration, such as emulsionsor syrups, can be produced using water, saccharides, such as sucrose,sorbitol, fructose, etc., glycols, such as polyethylene glycol,polypropylene glycol, etc., oils, such as sesame oil, olive oil, soybeanoil, etc., antiseptics, such as p-hydroxybenzoic acid esters, etc.,flavors, such as strawberry flavor, peppermint, etc., and the like.Furthermore, capsules, tablets, powders, granules and the like can beproduced using excipients, such as lactose, glucose, sucrose, mannitol,etc., disintegrators, such as starch, sodium alginate, etc .,lubricants, such as magnesium stearate, talc, etc., binders, such aspolyvinyl alcohol, hydroxypropylcellulose, gelatin, etc., surfactants,such as fatty acid esters, etc., plasticizers, such as glycerol, etc.,and the like.

Preparations suitable for parenteral administration preferably comprisean aqueous sterile preparation containing the active compound which isisotonic with blood of the recipient. For example, in the case ofinjections, a solution for injection is prepared using a carrier, suchas a salt solution, a glucose solution, or a mixture of a brine and aglucose solution, or the like.

Topical preparations are produced by dissolving or suspending the activecompound in at least one of media, such as mineral oil, petroleum,polyhydric alcohol, and the like, or in other bases usually used intopical pharmaceutical preparations.

Preparations for rectal administration are produced using usualcarriers, such as cacao butter, hydrogenated fat, hydrogenated fatcarboxylic acid, and the like, and are provided as suppositories.

Furthermore, at least one auxiliary component selected from the glycols,oils, flavors, antiseptics (including antioxidants), excipients,disintegrators, lubricants, binders, surfactants, plasticizers, and thelike which are exemplified in the oral preparations can also be added tothese parenteral preparations.

An effective dose and frequency of administration of Compound (I) or apharmaceutically acceptable salt thereof may vary depending on thedosage form, age and body weight of each patient, properties orseriousness of the symptoms to be treated and the like; however, thedose is generally 0.01 to 1,000 mg/man, preferably 5 to 500 mg/man, perday, and as to the administration frequency, it is preferred toadminister it once a day or by dividing the daily dose.

The compounds of the present invention can be directly applied to atherapeutic use as kinase inhibitors, particularly as those which arerelated to tyrosine kinase, for controlling kinase-dependent diseases inmammals. Compounds having an IC₅₀ value between 10 nM and 10 μM areparticularly preferred. It is possible to select a specific compound ofthe present invention which has the ability of inhibiting selectivelyone of the three protein kinase (a kinase which phosphorylates tyrosine,a kinase which phosphorylates tyrosine and threonine, and a kinase whichphosphorylates threonine). The tyrosine kinase-dependent diseasesinclude over-proliferative malfunctions which are initiated/maintainedby abnormal tyrosine kinase enzyme activity. Examples include psoriasis,pulmonary fibrosis, glomerulonephritis, cancers, atherosclerosis, andanti-angiogenesis (e.g., tumor proliferation or diabetic retinopathy).Although relationships of other classes of kinase to specific diseasesare not well known, it is considered that a selective tyrosinekinase-inhibiting compound has a useful therapeutic effect. Also, it isunderstood that other classes of kinase have their own usefultherapeutic effects. Quercetin, genistein and staurosporin which aretyrosine kinase inhibitors inhibit many other protein kinase in additionto the tyrosine kinase, and have strong cytotoxicity as a result of thelack of specificity for them. Accordingly, tyrosine kinase inhibitors(or inhibitors of other kinase) which are apt to induce undesirable sideeffects due to lack of selectivity can be identified using a usual testfor measuring cytotoxicity.

Examples, Reference Examples and Formulation Examples of the presentinvention are shown below; however, the present invention is not limitedthereto.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLE 1N-(4-Phenoxyphenyl)-4-(6-purinyl)-1-piperazinecarboxamide (Compound 1)

To a methylene chloride solution (50 mL) of4-[N-(4-phenoxyphenyl)carbamoyl]-1-piperazinecarboxylic acid tert-butylester (4.57 g, 11.51 mmol) produced in Reference Example 1,trifluoroacetic acid (60 mL) was added under ice-cooling, followed bystirring at the same temperature for2.5 hours. After concentration ofthe reaction solution, the resulting residue was dissolved in a mixedsolvent of dimethylformamide (24 mL) and triethylamine (8 mL), and6-chloropurine (2.58 g, 16.69 mmol) was added thereto, followed bystirring in argon atmosphere at room temperature overnight. The reactionsolution was poured into water, and the precipitated crystals wererecovered by filtration, washed with water, dried, and then purified bysilica gel column chromatography to give the target compound (3.41 g,8.22 mmol) as colorless crystals.

Yield: 71%

Melting point: 250-251° C.

¹H-NMR (DMSO-d₆) δ (ppm): 13.20 (1H, br), 8.65 (1H, brs), 8.25 (1H, s),8.17 (1H, s), 7.49 (2H, d, J=8.9 Hz), 7.39-7.33 (2H, m), 7.08 (1H, m),6.96-6.93 (4H, m), 4.27 (4H, m), 3.60-3.58 (4H, m).

FAB-Mass: 416 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1637, 1579, 1535, 1506, 1489, 1423,1227, 1022, 996, 937, 851, 748, 644.

EXAMPLE 2 N-(4-Nitrophenyl)-4-(6-purinyl)-1-piperazinecarboxamide(Compound 2)

To a methylene chloride solution (10 mL) of4-(6-purinyl)-1-piperazinecarboxylic acid tert-butyl ester (500 mg, 1.64mmol) disclosed in Japanese Published Unexamined Patent Application No.104074/89, trifluoroacetic acid (10 mL) was added under ice-cooling,followed by stirring at the same temperature for 1 hour. Afterconcentration of the reaction solution, the resulting residue wassubjected to an azeotropic treatment with toluene, and dissolved in amixed solvent of dimethylformamide (10 mL) and triethylamine (1.21 mL,8.68 mmol), and 4-nitrophenyl isocyanate (290 mg, 1.77 mmol) was addedthereto, followed by stirring overnight at room temperature in argonatmosphere. The reaction solution was poured into water, and theprecipitated crystals were recovered by filtration, washed with water,dried, and then purified by silica gel column chromatography to give thetarget compound (410 mg, 1.11 mmol) as colorless crystals.

Yield: 68%

Melting point: 270-275° C. (decomposed)

¹H-NMR (DMSO-d₆) δ (ppm): 13.09 (1H, br), 9.34 (1H, brs), 8.26 (1H, s),8.18 (1H, s), 8.17 (2H, d, J=9.2 Hz), 7.76 (2H, d, J=9.2 Hz), 4.29 (4H,m), 3.65-3.63 (4H, m).

FAB-Mass: 369 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1668, 1581, 1541, 1500, 1417, 1329,1296, 1240, 1174, 1111, 990, 939, 847.

EXAMPLE 3 N-Benzyl-4-(6-purinyl)-1-piperazinethiocarboxamide (Compound3)

The target compound was produced in the same manner as in Example 2,except that 4-nitrophenyl isocyanate was replaced with benzylisothiocyanate.

Yield: 70%

Melting point: 255-260° C.

¹H-NMR (DMSO-d₆) δ (ppm): 13.09 (1H, br), 8.33 (1H, brt, J=5.3 Hz), 8.25(1H, s), 8.17 (1H, s), 7.32-7.20 (5H, m), 4.84 (2H, d, J=5.3 Hz), 4.27(4H, m), 4.03-3.99 (4H, m).

FAB-Mass: 354 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1585, 1527, 1321, 1259, 1207.

EXAMPLE 4 4-(6-Purinyl)-N-(3-pyridylmethyl)-1-piperazinethiocarboxamidedihydrochloride (Compound 4)

A free form of the target compound was produced in the same manner as inExample 2, except that 4-nitrophenyl isocyanate was replaced with3-pyridylmethyl isothiocyanate. To an ethyl acetate suspension (20 mL)of the free form (443 mg, 1.25 mmol), a 4 N hydrogen chloride-ethylacetate solution (6.25 mL, 25 mmol) was added under ice-cooling,followed by stirring at the same temperature for 15 minutes. Crystalsobtained by filtering the reaction solution were washed with ethylacetate, and dried to give the target compound (471 mg, 1.21 mmol).

Yield: 73%

Melting point (hydrochloride): 178-185° C.

¹H-NMR (free form, DMSO-d₆) δ (ppm): 13.06 (1H, br), 8.55 (1H, d, J=2.3Hz), 8.45 (1H, dd, J=4.6 Hz, 1.7 Hz), 8.38 (1H, brt, J=5.3 Hz), 8.26(1H, s), 8.17 (1H, s), 7.74 (1H, ddd, J=7.9 Hz, 2.3 Hz, 1.7 Hz), 7.34(1H, dd, J=7.9 Hz, 4.6 Hz), 4.85 (2H, d, J=5.3 Hz), 4.29 (4H, m),4.04-4.00 (4H, m).

FAB-Mass: 355 ((M+1)⁺)

IR (hydrochloride, KBr tablet method) ν (cm⁻¹): 1633, 1539, 1410, 1257,1007, 930.

In the following Examples 5 to 7, the target compounds were produced inthe same manner as in Example 2, except that4-(6-purinyl)-1-piperazinecarboxylic acid tert-butyl ester was replacedwith 4-(2-amino-6-purinyl)-1-piperazinecarboxylic acid tert-butyl esterproduced in Reference Example 2, and that 4-nitrophenyl isocyanate wasreplaced with a corresponding isocyanate or isothiocyanate.

EXAMPLE 54-(2-Amino-6-purinyl)-N-(4-phenoxyphenyl)-1-piperazinecarboxamide(Compound 5)

Yield: 95%

Melting point: 244-258° C.

¹H-NMR (DMSO-d₆) δ (ppm): 12.23 (1H, br), 8.63 (1H, brs), 7.72 (1H, s),7.48 (2H, d, J=9.2 Hz), 7.39-7.33 (2H, m), 7.08 (1H, m), 6.98-6.93 (4H,m), 5.80 (2H, brs), 4.22-4.13 (4H, m), 3.59-3.54 (4H, m).

FAB-Mass: 431 ((M+1)⁺)

IR (KBr tablet method)v (cm⁻¹): 1641, 1601, 1568, 1508, 1489, 1414,1230, 997, 933, 835, 785, 743, 690, 635.

EXAMPLE 64-(2-Amino-6-purinyl)-N-(4-nitrophenyl)-1-piperazinecarboxamide(Compound 6)

Yield: 28%

Melting point: 208-214° C.

¹H-NMR (DMSO-d₆) δ (ppm): 9.31 (1H, brs), 8.17 (2H, d, J=9.2 Hz), 7.74(2H, d, J=9.2 Hz), 7.73 (1H, s), 5.80 (2H, brs), 4.20-4.19 (4H, m),3.60-3.58 (4H, m).

FAB-Mass: 384 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1662, 1610, 1572, 1489, 1329, 1301,1244, 1113, 997, 752.

EXAMPLE 7 4-(2-Amino-6-purinyl)-N-benzyl-1-piperazinethiocarboxamide(Compound 7)

Yield: 37%

Melting point: 242-245° C.

¹H-NMR (DMSO-d₆) δ (ppm): 12.23 (1H, brs), 8.31 (1H, brt, J=5.3 Hz),7.71 (1H, s), 7.32-7.20 (5H, m), 5.81 (2H, brs), 4.84 (2H, d, J=5.3 Hz),4.17 (4H, m), 3.96 (4H, m).

FAB-Mass: 369 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1614, 1578, 1527, 1491, 1450, 1398,1304, 1248, 1192, 1000, 944.

EXAMPLE 84-(2-Amino-6-purinyl)-N-(3-pyridylmethyl)-1-piperazinethiocarboxamidedihydrochloride (Compound 8)

The target compound was produced in the same manner as in Example 4,except that 4-(6-purinyl)-1-piperazinecarboxylic acid tert-butyl esterwas replaced with 4-(2-amino-6-purinyl)-1-piperazinecarboxylic acidtert-butyl ester produced in Reference Example 2.

Yield: 39%

Melting point (hydrochloride): 180-185° C. (decomposed)

¹H-NMR (free form, DMSO-d₆) δ (ppm): 12.22 (1H, br), 8.53 (1H, d, J=1.7Hz), 8.44 (1H, dd, J=4.6 Hz, 1.7 Hz), 8.34 (1H, brt, J=5.0 Hz), 7.72(1H, m), 7.71 (1H, s), 7.34 (1H, dd, J=7.6 Hz, 4.6 Hz), 5.80 (2H, brs),4.83 (2H, d, J=5.0 Hz), 4.21-4.14 (4H, m), 3.97-3.93 (4H, m).

FAB-Mass: 370 ((M+1)⁺)

IR (hydrochloride, KBr tablet method) ν (cm⁻¹): 1653, 1618, 1541, 1527,1524, 1000.

EXAMPLE 94-(9-Methyl-6-purinyl)-N-(4-phenoxyphenyl)-1-piperazinecarboxamide(Compound 9)

The target compound was produced in the same manner as in Example 2,except that 4-(6-purinyl)-1-piperazinecarboxylic acid tert-butyl esterwas replaced with 4-(9-methyl-6-purinyl)-1-piperazinecarboxylic acidtert-butyl ester disclosed in Japanese Published Unexamined PatentApplication No. 104074/89, and that 4-nitrophenyl isocyanate wasreplaced with 4-phenoxyphenyl isocyanate.

Yield: 91%

Melting point: 168-169° C.

¹H-NMR (CDCl₃) δ (ppm): 8.39 (1H, s), 7.73 (1H, s), 7.36-7.27 (4H, m),7.05 (1H, m), 6.98-6.95 (4H, m), 6.59 (1H, brs), 4.38 (4H, m), 3.82 (3H,s), 3.68-3.64 (4H, m).

FAB-Mass: 430 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1637, 1587, 1537, 1506, 1489, 1425,1252, 1227, 1001, 851, 748, 642.

EXAMPLE 10 (dl)-4-[9-(2-Tetrahydropyranyl)-6-purinyl]-N-(4-phenoxyphenyl)-1-piperazinecarboxamide(Compound 10)

The target compound was produced in the same manner as in Example 1,except that 6-chloropurine was replaced with commercially available (dl)-6-chloro-9-(2-tetrahydropyranyl)purine.

Yield: 74%

Melting point: 227-228° C.

¹H-NMR (CDCl₃) δ (ppm): 8.38 (1H, s), 7.98 (1H, s), 7.35-7.24 (4H, m),7.12-6.90 (5H, m), 6.48 (1H, brs), 5.74 (1H, dd, J=9.9 Hz, 2.5 Hz), 4.39(4H, m), 4.17 (1H, m), 3.83-3.61(5H, m), 2.12-1.95 (2H, m), 1.81-1.67(4H, m).

FAB-Mass: 500 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1630, 1587, 1533, 1508, 1473, 1425,1248, 1221, 995.

EXAMPLE 11N-(3-Pyridylmethyl)-4-{9-[N-(3-pyridylmethyl)thiocarbamoyl]-6-purinyl}-1-piperazinethiocarboxamide(Compound 11)

To a dimethylformamide solution (10 mL) of 6-(1-piperazinyl)purine (335mg, 1.64 mmol) produced in Reference Example 3, triethylamine (0.92 mL,6.60 mmol) and 3-picolyl isothiocyanate hydrobromide (916 mg, 3.96 mmol)were added, followed by stirring overnight at room temperature. Thereaction solution was poured into water, sodium chloride was addedthereto, and the precipitated crystals were recovered by filtration,washed with water, dried, and purified by silica gel columnchromatography to give the target compound (204 mg, 0.40 mmol).

Yield: 25%

Melting point: 143-144° C.

¹H-NMR (CDCl₃) δ (ppm): 11.93 (1H, brt, J=5.6 Hz), 8.93 (1H, d, J=5.6Hz), 8.69 (1H, d, J=2.3 Hz), 8.57 (1H, m), 8.54-8.45 (2H, m), 8.28 (1H,s), 7.81-7.76 (2H, m), 7.35-7.25 (2H, m), 6.44 (1H, brt, J=5.3 Hz), 5.07(2H, d, J=5.6 Hz), 4.95 (2H, d, J=5.3 Hz), 4.57-4.15 (4H, br), 4.10-4.07(4H, m).

FAB-Mass: 505 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1728, 1601, 1560, 1477, 1425, 1379,1325, 1254, 789, 712.

EXAMPLE 124-(5-Carbamoyl-1,3-dimethyl-4-1H-pyrazolo[3,4-b]pyridyl)-N-(4-phenoxyphenyl)-1-piperazinecarboxamide(Compound 12)

The target compound was produced in the same manner as in Example 2,except that 4-(6-purinyl)-1-piperazinecarboxylic acid tert-butyl esterwas replaced with4-(5-carbamoyl-1,3-dimethyl-4-1H-pyrazolo[3,4-b]pyridyl)-1-piperazinecarboxylicacid tert-butyl ester produced in Reference Example 4, and that4-nitrophenyl isocyanate was replaced with 4-phenoxyphenyl isocyanate.

Yield: quantitative

Melting point: 248-250° C.

¹H-NMR (DMSO-d₆) δ (ppm): 8.69 (1H, s), 8.26 (1H, s), 7.99 (1H, brs),7.58 (1H, brs), 7.49 (2H, d, J=8.9 Hz), 7.36 (2H, m), 7.08 (1H, m),6.96-6.93 (4H, m), 3.92 (3H, s), 3.66 (4H, m), 3.30 (4H, m), 2.64 (3H,s).

FAB-Mass: 486 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1649, 1583, 1558, 1508, 1489, 1417,1381, 1248, 1228.

EXAMPLE 134-(1-Methyl-4-1H-pyrazolo[3,4-d]pyrimidinyl)-N-(4-phenoxyphenyl)-1-piperazinecarboxamide(Compound 13)

To a dimethylformamide solution (10 mL) of1-methyl-4-(1-piperazinyl)-1H-pyrazolo[3,4-d]pyrimidine (482 mg, 2.21mmol) produced in Reference Example 5, 4-phenoxyphenyl isocyanate (0.47mL, 2.23 mmol) was added, followed by stirring overnight at roomtemperature. The reaction solution was poured into water, and theprecipitated crystals were recovered by filtration, washed with water,dried, and then purified by silica gel column chromatography to give thetarget compound (770 mg, 1.79 mmol) as colorless crystals.

Yield: 81%

Melting point: 155-156° C.

¹H-NMR (CDCl₃) δ (ppm): 8.39 (1H, s), 7.93 (1H, s), 7.35-7.25 (4H, m),7.06 (1H, m), 6.97-6.93 (4H, m), 6.75 (1H, brs), 4.12-4.08 (4H, m), 4.03(3H, s), 3.79-3.75 (4H, m).

FAB-Mass: 430 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1664, 1578, 1506,1489, 1416, 1342,1292, 1230, 993, 924, 750.

In the following Examples 14 and 15, the target compounds were producedin the same manner as in Example 13, except that 4-phenoxyphenylisocyanate was replaced with a corresponding isothiocyanate.

EXAMPLE 14 N-Benzyl-4-(1-methyl-4-1H-pyrazolo[3,4-d]pyrimidinyl)-1-piperazinethiocarboxamide (Compound15)

Yield: 78%

Melting point: 175-176° C.

¹H-NMR (CDCl₃) δ (ppm): 8.36 (1H, m), 7.91 (1H, s), 7.35-7.29 (5H, m),5.86 (1H, brt, J=5.0 Hz), 4.88 (2H, d, J=5.0 Hz), 4.17 (8H, m), 4.01(3H, s).

FAB-Mass: 368 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹) 1581, 1558, 1541, 1525, 1408, 1383,1336.

EXAMPLE 154-(1-Methyl-4-1H-pyrazolo[3,4-d]pyrimidinyl)-N-(3-pyridylmethyl)-1-piperazinethiocarboxamide(Compound 14)

Yield: 92%

Melting point: 210-211° C.

¹H-NMR (CDCl₃) δ (ppm): 8.39 (2H, m) , 8.33 (1H, s), 7.91 (1H, s), 7.77(1H, d, J=7.9 Hz), 7.24 (1H, dd, J=7.9 Hz, 5.0 Hz), 7.14 (1H, brt, J=5.3Hz), 4.91 (2H, d, J=5.3 Hz), 4.18-4.16 (8H, m), 3.99 (3H, s).

FAB-Mass: 369 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1560, 1446, 1417, 1363, 1333, 1275,1184, 989, 787.

EXAMPLE 16N-(4-Phenoxyphenyl)-4-(1-phenyl-4-1H-pyrazolo[3,4-d]pyrimidinyl)-1-piperazinecarboxamide(Compound 16)

The target compound was produced in the same manner as in Example 13,except that 1-methyl-4-(1-piperazinyl)-1H-pyrazolo[3,4-d]pyrimidine wasreplaced with 1-phenyl-4-(1-piperazinyl)-1H-pyrazolo[3,4-d]pyrimidineproduced in Reference Example 6

Yield: 91%

FAB-Mass: 492 ((M+1)⁺)

EXAMPLE 174-(1-Phenyl-4-1H-pyrazolo[3,4-d]pyrimidinyl)-N-(3-pyridylmethyl)-1-piperazinethiocarboxamidedihydrochloride (Compound 17)

A free form of the target compound was produced in the same manner as inExample 13, except that1-methyl-4-(1-piperazinyl)-1H-pyrazolo[3,4-d]pyrimidine was replacedwith 1-phenyl-4-(1-piperazinyl)-1H-pyrazolo[3,4-d]pyrimidine produced inReference Example 6, and that 4-phenoxyphenyl isocyanate was replacedwith 3-pyridylmethyl isocyanate. Then, the hydrochloride treatment wascarried out in the same manner as in Example 4 to give the targetcompound.

Yield: 56%

Melting point (hydrochloride): 160-163° C.

¹H-NMR (free form, DMSO-d₆) δ (ppm): 8.58-8.56 (2H, s), 8.45-8.42 (2H,m), 8.32 (1H, s), 8.20 (2H, d, J=7.6 Hz), 7.74 (1H, m), 7.59-7.53 (2H,m), 7.39-7.32 (2H, m), 4.84 (2H, d, J=5.0 Hz), 4.13 (8H, m).

FAB-Mass: 431 ((M+1)⁺)

IR (hydrochloride, KBr tablet method) ν (cm⁻¹) 1645, 1593, 1537, 1500,1410, 1221, 974, 770, 681.

In the following Examples 18 and 19, the target compounds were producedin the same manner as in Example 13, except that1-methyl-4-(1-piperazinyl)-1H-pyrazolo[3,4-d]pyrimidine was replacedwith 4-(1-piperazinyl)-5,6-tetramethylenethieno[2,3-d]pyrimidineproduced in Reference Example 7, and that 4-phenoxyphenyl isocyanate wasreplaced with a corresponding isocyanate or isothiocyanate.

EXAMPLE 18N-(4-Phenoxyphenyl)-4-(5,6-tetramethylene-4-thieno[2,3-d]-pyrimidinyl)-1-piperazinecarboxamide (Compound 18)

Yield: 94%

Melting point: 183-184° C.

¹H-NMR (CDCl₃ ) δ (ppm): 8.55 (1H, s), 7.35-7.26 (4H, m), 7.07 (1H, m),6.99-6.96 (4H, m), 6.50 (1H, brs) , 3.70-3.67 (4H, m), 3.49-3.45 (4H,m), 2.96-2.88 (4H, m), 2.00-1.92 (2H, m), 1.89-1.81 (2H, m).

FAB-Mass: 486 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1643, 1531, 1506, 1489, 1416, 1225,991.

EXAMPLE 19N-(4-Chlorobenzyl)-4-(5,6-tetramethylene-4-thieno[2,3-d]pyrimidinyl)-1-piperazinecarboxamide(Compound 19)

Yield: quantitative

Melting point: 185-186° C.

¹H-NMR (CDCl₃) δ (ppm): 8.42 (1H, s), 7.23 (4H, s), 6.72 (1H, brt, J=5.0Hz), 4.86 (2H, d, J=5.0 Hz), 4.10-4.02 (4H, m), 3.49-3.45 (4H, m),2.90-2.85 (4H, m), 1.93-1.92 (2H, m), 1.81-1.80 (2H, m).

FAB-Mass: 458 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1531, 1498, 1435, 1381, 1325, 1269,1250, 1206, 984, 972.

In the following Examples 20 and 21, the target compounds were producedin the same manner as in Example 2, except that4-(6-purinyl)-piperazinecarboxylic acid tert-butyl ester was replacedwith 4-(4-pyrido[2,3-d]pyrimidinyl)-1-piperazinecarboxylic acidtert-butyl ester produced in Reference Example 8, and that 4-nitrophenylisocyanate was replaced with a corresponding isocyanate orisothiocyanate.

EXAMPLE 20N-(4-Phenoxyphenyl)-4-(4-pyrido[2,3-d]pyrimidinyl)-1-piperazinecarboxamide(Compound 20)

Yield: 76%

Melting point: 104-106° C.

¹H-NMR (CDCl₃) δ (ppm): 9.06 (1H, dd, J=4.3 Hz, 1.3 Hz), 8.86 (1H, s),8.26 (1H, dd, J=8.3 Hz, 1.3 Hz), 7.42 (1H, dd, J=8.3 Hz, 4.3 Hz),7.37-7.13 (4H, m), 7.09-6.92 (6H, m), 3.96-3.92 (4H, m), 3.80-3.76 (4H,m).

FAB-Mass: 427 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1664, 1595, 1570, 1541, 1508, 1491,1414, 1329, 1228, 993, 792, 756.

EXAMPLE 21N-Benzyl-4-(4-pyrido[2,3-d]pyrimidinyl)-1-piperazinethiocarboxamide(Compound 21)

Yield: 59%

Melting point: 169-170° C.

¹H-NMR (CDCl₃) δ (ppm): 9.03 (1H, dd, J=4.3 Hz, 1.7 Hz), 8.80 (1H, s),8.27 (1H, dd, J=8.2 Hz, 1.7 Hz), 7.42-7.29 (6H, m), 6.04 (1H, brt, J=5.0Hz), 4.90 (2H, d, J=5.0 Hz), 4.18-4.14 (4H, m), 4.08-4.06 (4H, m).

FAB-Mass: 365 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1568, 1541, 1498, 1444, 1338, 1273.

EXAMPLE 22N-(4-Phenoxyphenyl)-4-(6-fluoro-4-pyrido[3,4-d]pyrimidinyl)-1-piperazinecarboxamide(Compound 22)

The target compound was produced in the same manner as in Example 2,except that 4-(6-purinyl)-1-piperazinecarboxylic acid tert-butyl esterwas replaced with4-(6-fluoro-4-pyrido[3,4-d]pyrimidinyl)-1-piperazinecarboxylic acidtert-butyl ester produced in Reference Example 9, and 4-nitrophenylisocyanate was replaced with 4-phenoxyphenyl isocyanate.

Yield: 86%

¹H-NMR (CDCl₃) δ (ppm): 9.05 (1H, s), 8.78 (1H, s), 7.35-7.27 (5H, m),7.07 (1H, m), 7.01-6.96 (4H, m), 6.51 (1H, brs), 3.99-3.95 (4H, m),3.79-3.75 (4H, m).

FAB-Mass: 445 ((M+1)⁺)

EXAMPLE 23N-(4-Phenoxyphenyl)-4-[3-amino-1-(2,6-naphthyridinyl)]-1-piperazinecarboxamide(Compound 23)

The target compound was produced in the same manner as in Example 1,except that 6-chloropurine was replaced with3-amino-1-bromo-2,6-naphthyridine.

Yield: 8%

¹H-NMR (CDCl₃) δ (ppm): 8.95 (1H, s), 8.27 (1H, d, J=5.9 Hz), 7.58 (1H,d, J=5.9 Hz), 7.36-7.29 (4H, m), 7.07 (1H, m), 7.01-6.97 (4H, m), 6.40(1H, s), 6.39 (1H, brs), 4.43 (2H, br), 3.76-3.72 (4H, m), 3.54-3.49(4H, m).

FAB-Mass: 441 ((M+1)⁺)

In the following Examples 24 to 27, the target compounds were producedin the same manner as in Example 2, except that 4-nitrophenyl isocyanatewas replaced with a corresponding isocyanate or isothiocyanate.

EXAMPLE 24 N-(4-Cyanophenyl)-4-(6-purinyl)-1-piperazinecarboxamide(Compound 24)

Yield: 64%

¹H-NMR (DMSO-d₆) δ (ppm): 9.11 (1H, brs), 8.25 (1H, s), 8.16 (1H, s),7.69 (4H, s), 4.28 (4H, br), 3.63 (4H, m).

FAB-Mass: 349 ((M+1)⁺)

EXAMPLE 25 N-(4-Isopropoxyphenyl)-4-(6-purinyl)-1-piperazinecarboxamide(Compound 25)

Yield: 66%

¹H-NMR (DMSO-d₆) δ (ppm): 8.44 (1H, brs), 8.25 (1H, s), 8.16 (1H, s),7.33 (2H, d, J=8.9 Hz), 6.81 (2H, d, J=8.9 Hz), 4.50 (1H, m), 4.26 (4H,m), 3.58 (4H, m), 1.24 (6H, d, J=5.9 Hz).

FAB-Mass: 382 ((M+1)⁺)

EXAMPLE 26N-(3,4-Methylenedioxybenzyl)-4-(6-purinyl)-1-piperazinethiocarboxamide(Compound 26)

Yield: 96%

¹H-NMR (DMSO-d₆) δ (ppm): 8.24 (1H, s), 8.24 (1H, brt, J=5.3 Hz), 8.15(1H, s), 6.91 (1H, s), 6.86-6.77 (2H, m), 5.97 (2H, s), 4.72 (2H, d,J=5.3 Hz), 4.26 (4H, m), 3.99 (4H, m).

FAB-Mass: 398 ((M+1)⁺)

EXAMPLE 27 N-(4-Methoxybenzyl)-4-(6-purinyl)-1-piperazinethiocarboxamide(Compound 27)

Yield: 55%

¹H-NMR (DMSO-d₆) δ (ppm): 13.06 (1H, br), 8.25 (1H, s), 8.25 (1H, br),8.16 (1H, s), 7.26 (2H, d, J=8.3 Hz), 6.88 (2H, d, J=8.3 Hz), 4.76 (2H,d, J=5.3 Hz), 4.26 (4H, br), 3.99 (4H, br), 3.73 (3H, s).

FAB-Mass: 384 ((M+1)⁺)

EXAMPLE 28N-Benzyl-N′-cyano-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamidine(Compound 28)

The target compound was produced in the same manner as in Example 41described later, except that piperonylamine was replaced withbenzylamine.

Yield: 64%

¹H-NMR (CDCl₃) δ (ppm): 8.65 (1H, s), 7.39-7.19 (6H, m), 7.04 (1H, s),5.76 (1H, brt, J=5.6 Hz), 4.59 (2H, d, J=5.6 Hz), 4.02 (3H, s), 3.97(3H, s), 3.79-3.69 (8H, m).

FAB-Mass: 432 (M⁺+1)

EXAMPLE 29N-(2-Chlorobenzyl)-N′-cyano-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamidine(Compound 29)

To an ethanol solution (10 mL) of Compound 65 produced in Example 65described later (0.60 g, 1.61 mmol), 2-chlorobenzylamine (0.97 mL, 8.04mmol) was added, followed by heating under reflux for 10 hours.2-Chlorobenzylamine (0.97 mL, 8.04 mmol) was further added thereto,followed by heating under reflux for 6.5 hours. The reaction solutionwas concentrated, and the resulting residue was purified by silica gelcolumn chromatography to give the target compound (0.85 g, 1.83 mmol).

Yield: quantitative

¹H-NMR (DMSO-d₆) δ (ppm): 8.65 (1H, s), 7.47-7.15 (5H, m), 7.04 (1H, s),5.78 (1H, brt, J=5.6 Hz), 4.68 (2H, d, J=5.6 Hz), 4.02 (3H, s), 3.98(3H, s), 3.77-3.70 (8H, m).

FAB-Mass: 468 ((M+3)⁺), 466 ((M+1)⁺)

EXAMPLE 30N-(3-Chlorobenzyl)-N′-cyano-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamidine(Compound 30)

To an isopropanol solution (10 mL) of Compound 67 produced in Example 67described later (0.50 g, 1.20 mmol), 3-chlorobenzylamine (0.44 mL, 3.60mmol) was added, followed by heating under reflux for 6 hours. Thereaction solution was concentrated and the resulting residue waspurified by silica gel column chromatography to give the target compound(0.66 g, 1.42 mmol).

Yield: quantitative

¹H-NMR (DMSO-d₆) δ (ppm): 8.56 (1H, s), 7.93 (1H, brt, J=4.6 Hz),7.39-7.28 (4H, m), 7.24 (1H, s), 7.1.9 (1H, s), 4.52 (2H, d, J=4.6 Hz),3.93 (3H, s), 3.93 (3H, s), 3.74 (8H, m).

FAB-Mass: 468 ((M+3)⁺), 466 ((M+1)⁺)

EXAMPLE 31N-(4-Chlorobenzyl)-N′-cyano-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamidine(Compound 31)

To an ethanol solution (10 mL) of Compound 67 produced in Example 67described later (438 mg, 1.05 mmol), 4-chlorobenzylamine (0.64 mL, 5.26mmol) was added, followed by heating under reflux for 7.5 hours. Thereaction solution was concentrated and the resulting residue waspurified by silica gel column chromatography to give the target compound(0.58 g, 1.25 mmol).

Yield: quantitative

¹H-NMR (CDCl₃) δ (ppm): 8.65 (1H, s), 7.35-7.18 (5H, m), 7.05 (1H, s),5.49 (1H, brt, J=5.6 Hz), 4.57 (2H, d, J=5.6 Hz), 4.02 (3H, s), 3.98(3H, s), 3.78-3.71 (8H, m).

FAB-Mass: 468 ((M+3)⁺), 466 ((M+1)⁺)

EXAMPLE 32N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-fluorobenzyl)-1-piperazinecarboxamidine(Compound 32)

The target compound was produced in the same manner as in Example 30,except that 3-chlorobenzylamine was replaced with 4-fluorobenzylamine.

Yield: 80%

¹H-NMR (DMSO-d₆) δ (ppm): 8.56 (1H, s), 7.93 (1H, brs), 7.40-7.34 (2H,m), 7.24 (1H, s), 7.22-7.14 (3H, m), 4.50 (2H, br), 3.93 (3H, s), 3.93(3H, s), 3.72 (8H, m).

FAB-Mass: 450 ((M+1)⁺)

EXAMPLE 33N-(4-Bromobenzyl)-N′-cyano-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamidine(Compound 33)

The target compound was produced in the same manner as in Example 30,except that 3-chlorobenzylamine was replaced with 4-bromobenzylaminehydrochloride, and that the reaction was carried out after producing afree form of the hydrochloride in the system using triethylamine.

Yield: 68%

¹H-NMR (DMSO-d₆) δ (ppm): 8.56 (1H, s), 7.95 (1H, brt, J=5.3 Hz), 7.55(2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 7.24 (1H, s), 7.19 (1H, s),4.49 (2H, d, J=5.3 Hz), 3.93 (3H, s), 3.93 (3H, s), 3.73 (8H, m).

FAB-Mass: 512 ((M+3)⁺), 510 ((M+1)⁺)

In the following Examples 34 to 37, the target compounds were producedin the same manner as in Example 30, except that 3-chlorobenzylamine wasreplaced with a corresponding amine.

EXAMPLE 34N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-methylbenzyl)-1-piperazinecarboxamidine(Compound 34)

Yield: 81%

¹H-NMR (DMSO-d₆) δ (ppm): 8.56 (1H, s), 7.90 (1H, brs), 7.23-7.14 (6H,m), 4.49 (2H, s), 3.93 (3H, s), 3.93 (3H, s), 3.72 (8H, br), 2.29 (3H,s).

FAB-Mass: 446 ((M+1)⁺)

EXAMPLE 35N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-isopropylbenzyl)-1-piperazinecarboxamidine(Compound 35)

Yield: 69%

¹H-NMR (CDCl₃) δ (ppm): 8.66 (1H, s), 7.26 (4H, s), 7.26 (1H, s), 7.05(1H, s), 5.10 (1H, brt, J=5.3 Hz), 4.58 (2H, d, J=5.3 Hz), 4.02 (3H, s),3.99 (3H, s), 3.79-3.70 (8H, m), 2.91 (1H, m), 1.24 (6H, d, J=6.9 Hz).

FAB-Mass: 474 ((M+1)⁺)

EXAMPLE 36N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-methoxybenzyl)-1-piperazinecarboxamidine(Compound 36)

Yield: 91%

¹H-NMR (CDCl₃) δ (ppm): 8.63 (1H, s), 7.25 (2H, d, J=8.6 Hz), 7.23 (1H,s), 7.04 (1H, s), 6.85 (2H, d, J=8.6 Hz), 5.94 (1H, brt, J=5.6 Hz), 4.53(2H, d, J=5.6 Hz), 4.01 (3H, s), 3.97 (3H, s), 3.76 (3H, s), 3.72 (8H,m).

FAB-Mass: 462 ((M+1)⁺)

EXAMPLE 37N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-methylthiobenzyl)-1-piperazinecarboxamidine(Compound 37)

Yield: 87%

¹H-NMR (DMSO-d₆) δ (ppm): 8.56 (1H, s), 7.91 (1H, brs), 7.26-7.24 (5H,m), 7.19 (1H, s), 4.48 (2H, s), 3.93 (3H, s), 3.93 (3H, s), 3.72 (8H,br), 2.46 (3H, s).

FAB-Mass: 478 ((M+1)⁺)

EXAMPLE 38N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-mesylbenzyl)-1-piperazinecarboxamidine(Compound 38)

The target compound was produced in the same manner as in Example 30,except that 3-chlorobenzylamine was replaced with 4-mesylbenzylaminehydrochloride, and that the reaction was carried out after producing afree form of the hydrochloride in the system using triethylamine.

Yield: 67%

¹H-NMR (DMSO-d₆) δ (ppm): 8.57 (1H, s), 8.04 (1H, brt, J=5.3 Hz), 7.91(2H, d, J=8.6 Hz), 7.58 (2H, d, J=8.6 Hz), 7.24 (1H, s), 7.20 (1H, s),4.61 (2H, d, J=5.3 Hz), 3.94 (3H, s), 3.93 (3H, s), 3.76 (8H, m), 3.21(3H, s).

FAB-Mass: 510 ((M+1)⁺)

EXAMPLE 39N-(1-Butyl)-N′-cyano-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamidine(Compound 39)

The target compound was produced in the same manner as in Example 30,except that 3-chlorobenzylamine was replaced with 1-butylamine.

Yield: 91%

¹H-NMR (CDCl₃) δ (ppm): 8.67 (1H, s), 7.28 (1H, s), 7.07 (1H, s), 5.21(1H, brt, J=5.6 Hz), 4.03 (3H, s), 3.99 (3H, s), 3.79-3.70 (8H, m), 3.45(2H, dt, J=7.3 Hz, 5.6 Hz), 1.61 (2H, tt, J=7.3 Hz, 7.3 Hz), 1.40 (2H,tq, J=7.6 Hz, 7.3 Hz), 0.95 (3H, t, J=7.6 Hz).

FAB-Mass: 398 ((M+1)⁺)

EXAMPLE 40N′-Cyano-N-cyclohexyl-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamidine(Compound 40)

The target compound was produced in the same manner as in Example 30,except that 3-chlorobenzylamine was replaced with cyclohexylamine.

Yield: 75%

¹H-NMR (CDCl₃) δ (ppm): 8.67 (1H, s), 7.26 (1H, s), 7.07 (1H, s), 4.90(1H, d, J=8.3 Hz), 4.03 (3H, s), 3.99 (3H, s), 3.80-3.70 (9H, m),2.04-1.17 (10H, m).

FAB-Mass: 424 ((M+1)⁺)

EXAMPLE 41N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-(3,4-methylenedioxybenzyl)-1-piperazinecarboxamidine(Compound 41)

To a dimethylformamide solution (20 mL) of Compound 65 produced inExample 65 described later (1.63 g, 4.38 mmol), piperonylamine (2.98 mL,23.9 mmol) was added, followed by stirring under heating at 80° C. for13 hours. Piperonylamine (2.98 mL, 23.9 mmol) was further added thereto,followed by stirring at the same temperature for 3.5 hours. After thereaction solution was allowed to stand for cooling, the reactionsolution was poured into water, sodium chloride was added thereto, andthe precipitated crystals were recovered by filtration, washed withwater, dried, and then purified by silica gel column chromatography togive the target compound (0.53 g, 1.12 mmol).

Yield: 25%

¹H-NMR (CDCl₃) δ (ppm): 8.66 (1H, s), 7.25 (1H, s), 7.06 (1H, s),6.82-6.72 (3H, m), 5.96 (2H, s), 5.26 (1H, brt, J=5.0 Hz), 4.51 (2H, d,J=5.0 Hz), 4.02 (3H, s), 3.98 (3H, s), 3.78-3.70 (8H, m).

FAB-Mass: 476(M⁺+1)

EXAMPLE 42N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-[2-(3,4-methylenedioxyphenyl)ethyl]-1-piperazinecarboxamidine(Compound 42)

The target compound was produced in the same manner as in Example 30,except that 3-chlorobenzylamine was replaced with2-(3,4-methylenedioxyphenyl)ethylamine hydrochloride, and that thereaction was carried out after producing a free form of thehydrochloride in the system using triethylamine.

Yield: 68%

¹H-NMR (DMSO-d₆) δ (ppm): 8.56 (1H, s), 7.41 (1H, br), 7.24 (1H, s),7.18 (1H, s), 6.85 (1H, s), 6.84 (1H, d, J=7.9 Hz), 6.70 (1H, d, J=7.9Hz), 5.97 (2H, s), 3.94 (3H, s), 3.93 (3H, s), 3.66-3.64 (8H, m), 3.54(2H, m), 2.77 (2H, t, J=6.9 Hz).

FAB-Mass: 490 ((M+1)⁺)

In the following Examples 43 to 49, the target compounds were producedin the same manner as in Example 30, except that 3-chlorobenzylamine wasreplaced with a corresponding amine.

EXAMPLE 43N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-(2-pyridylmethyl)-1-piperazinecarboxamidine(Compound 43)

Yield: 86%

¹H-NMR (CDCl₃) δ (ppm): 8.67 (1H, s), 8.54 (1H, dd, J=5.0 Hz, 1.7 Hz),7.73 (1H, ddd, J=7.9 Hz, 7.6 Hz, 1.7 Hz), 7.35-7.24 (3H, m), 7.10 (1H,s), 7.06 (1H, brt, J=4.3 Hz), 4.85 (2H, d, J=4.3 Hz), 4.03 (3H, s), 4.00(3H, s), 3.83 (8H, m).

FAB-Mass: 433 ((M+1)⁺)

EXAMPLE 44N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-(3-pyridylmethyl)-1-piperazinecarboxamidine(Compound 44)

Yield: 75%

¹H-NMR (CDCl₃) δ (ppm): 8.61 (1H, s), 8.52 (1H, d, J=2.0 Hz), 8.43 (1H,dd, J=5.0 Hz, 1.7 Hz), 7.70 (1H, ddd, J=7.9 Hz, 2.0 Hz, 1.7 Hz),7.26-7.22 (3H,m), 7.21 (1H,s), 7.05 (1H,s), 4.58 (2H, d, J=5.6 Hz), 4.00(3H, s), 3.96 (3H, s), 3.75 (8H, m).

FAB-Mass: 433 ((M+1)⁺)

EXAMPLE 45N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-pyridylmethyl)-1-piperazinecarboxamidine(Compound 45)

Yield: quantitative

¹H-NMR (DMSO-d₆) δ (ppm): 8.57 (1H, s), 8.53 (2H, d, J=5.9 Hz), 7.98(1H, brt, J=4.6 Hz), 7.31 (2H, d, J=5.9 Hz), 7.24 (1H, s), 7.20 (1H, s),4.54 (2H, d, J=4.6 Hz), 3.94 (3H, s), 3.94 (3H, s), 3.77 (8H, m).

FAB-Mass: 433 ((M+1)⁺)

EXAMPLE 46N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-[2-(3-pyridyl)-ethyl]-1-piperazinecarboxamidine(Compound 46)

Yield: 81%

¹H-NMR (CDCl₃) δ (ppm): 8.64 (1H, s), 8.47-8.45 (2H, m), 7.62 (1H, ddd,J=7.9 Hz, 2.0 Hz, 1.7 Hz), 7.27 (1H, dd, J=7.9 Hz, 5.0 Hz), 7.24 (1H,s), 7.05 (1H, s), 5.84 (1H, brt, J=5.6 Hz), 4.02 (3H, s), 3.98 (3H, s),3.78-3.65 (10H, m), 2.98 (2H, t, J=6.9 Hz).

FAB-Mass: 447 ((M+1)⁺)

EXAMPLE 47N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-[2-(4-pyridyl)-ethyl]-1-piperazinecarboxamidine(Compound 47)

Yield: 64%

¹H-NMR (CDCl₃) δ (ppm): 8.60 (1H, s), 8.44 (2H, d, J=4.3 Hz), 7.22 (1H,s), 7.18 (2H, d, J=4.3 Hz), 7.04 (1H, s), 6.61 (1H, br), 4.01 (3H, s),3.97 (3H, s), 3.74-3.67 (10H, m), 2.96 (2H, t, J=6.9 Hz).

FAB-Mass: 447 ((M+1)⁺)

EXAMPLE 48N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-(5-methyl-2-pyrazinyl)-1-piperazinecarboxamidine1-piperazinecarboxamidine (Compound 48)

Yield: quantitative

¹H-NMR (CDCl₃) δ (ppm): 8.66 (1H, s), 8.54 (1H, s), 8.39 (1H, s), 7.26(1H, s), 7.08 (1H, s), 6.69 (1H, brt, J=4.0 Hz), 4.81 (2H, d, J=4.0 Hz),4.03 (3H, s), 4.00 (3H, s), 3.82 (8H, m), 2.58 (3H, s).

FAB-Mass: 448 ((M+1)⁺)

EXAMPLE 49N′-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-N-furfuryl-1-piperazinecarboxamidine(Compound 49)

Yield: 59%

¹H-NMR (CDCl₃) δ (ppm): 8.64 (1H, s), 7.35 (1H, m), 7.24 (1H, s), 7.05(1H, s), 6.31-6.12 (3H, m), 4.61 (2H, d, J=5.6 Hz), 4.01 (3H, s), 3.98(3H, s), 3.75 (8H, m).

FAB-Mass: 422 ((M+1)⁺)

EXAMPLE 504-{4-[1-(2-Chlorobenzylamino)-2,2-dicyanovinyl]-1-piperazinyl}-6,7-dimethoxyquinazoline(Compound 50)

To an acetonitrile solution (10 mL) of Compound 64 produced in Example64 described later (0.50 g, 1.26 mmol), 2-chlorobenzylamine (0.76 mL,6.30 mmol) was added, followed by heating under reflux for 5.5 hours.After the reaction solution was allowed to stand for cooling, theprecipitated crystals were recovered by filtration, washed withacetonitrile, and then dried to give the target compound (0.81 g, 1.66mmol).

Yield: quantitative

¹H-NMR (DMSO-d₆) δ (ppm): 8.82 (1H, s), 8.14 (1H, brt, J=5.0 Hz),7.54-7.49 (2H, m), 7.44 (1H, s), 7.41-7.37 (3H, m), 4.59 (2H, d, J=5.0Hz), 4.26 (4H, m), 3.98 (3H, s), 3.96 (3H, s), 3.78 (4H, m).

FAB-Mass: 492 ((M+3)⁺), 490 ((M+1)⁺)

In the following Examples 51 to 57, the target compounds were producedin the same manner as in Example 50, except that 2-chlorobenzylamine wasreplaced with a corresponding amine.

EXAMPLE 514-{4-[1-(3-Chlorobenzylamino)-2,2-dicyanovinyl]-1-piperazinyl}-6,7-dimethoxyquinazoline(Compound 51)

Yield: 45%

¹H-NMR (DMSO-d₆) δ (ppm): 8.58 (1H, s), 8.09 (1H, brt, J=5.0 Hz),7.48-7.33 (4H, m), 7.24 (1H, s), 7.20 (1H, s), 4.52 (2H, d, J=5.0 Hz),3.94 (3H, s), 3.94 (3H, s), 3.75-3.70 (8H, m).

FAB-Mass: 492 ((M+3)⁺), 490 ((M+1)⁺)

EXAMPLE 524-{4-[1-(4-Chlorobenzylamino)-2,2-dicyanovinyl]-1-piperazinyl}-6,7-dimethoxyquinazoline(Compound 52)

Yield: 62%

¹H-NMR (CDCl₃) δ (ppm): 8.66 (1H, s), 7.38 (2H, d, J=8.6 Hz), 7.27 (1H,s), 7.25 (2H, d, J=8.6 Hz), 7.04 (1H, s), 5.46 (1H, brt, J=5.6 Hz), 4.44(2H, d, J=5.6 Hz), 4.03 (3H, s), 3.99 (3H, s), 3.82-3.78 (4H, m),3.66-3.64 (4H, m).

FAB-Mass: 492 ((M+3)⁺), 490 ((M+1)⁺)

EXAMPLE 534-{4-[2,2-Dicyano-1-(4-methoxybenzylamino)vinyl]-1-piperazinyl}-6,7-dimethoxyquinazoline(Compound 53)

Yield: 48%

¹H-NMR (DMSO-d₆) δ (ppm): 8.57 (1H, s), 8.02 (1H, brs), 7.31 (2H, d,J=8.6 Hz), 7.24 (1H, s), 7.19 (1H, s), 6.95 (2H, d, J=8.6 Hz), 4.43 (2H,s), 3.93 (3H, s), 3.93 (3H, s), 3.76-3.68 (8H, m), 3.33 (3H, s).

FAB-Mass: 486 ((M+1)⁺)

EXAMPLE 544-{4-[2,2-Dicyano-1-(3,4-methylenedioxybenzylamino)vinyl]-1-piperazinyl}-6,7-dimethoxyquinazoline(Compound 54)

Yield: 48%

¹H-NMR (DMSO-d₆) δ (ppm): 8.57 (1H, s), 7.99 (1H, brs), 7.24 (1H, s),7.19 (1H, s), 6.97 (1H, s), 6.93-6.87 (2H, m), 6.02 (2H, s), 4.40 (2H,s), 3.93 (3H, s), 3.93 (3H, s), 3.72-3.68 (8H, m).

FAB-Mass: 500 ((M+1)⁺)

EXAMPLE 554-{4-[2,2-Dicyano-1-(2-pyridylmethylamino)vinyl]-1-piperazinyl}-6,7-dimethoxyquinazoline(Compound 55)

Yield: 60%

¹H-NMR (DMSO-d₆) δ (ppm): 8.60 (1H, s), 8.57 (1H, dd, J=5.0 Hz, 2.0 Hz),8.07 (1H, brt, J=5.3 Hz), 7.83 (1H, ddd, J=7.9 Hz, 7.6 Hz, 2.0 Hz), 7.45(1H, d, J=7.9 Hz), 7.33 (1H, dd, J=7.6 Hz, 5.0 Hz), 7.25 (1H, s), 7.23(1H, s), 4.64 (2H, d, J=5.3 Hz), 3.94 (3H, s), 3.94 (3H, s), 3.80-3.78(8H, m).

FAB-Mass: 457 ((M+1)⁺)

EXAMPLE 564-{4-[2,2-Dicyano-1-(3-pyridylmethylamino)vinyl]-1-piperazinyl}-6,7-dimethoxyquinazoline(Compound 56)

Yield: 77%

¹H-NMR (DMSO-d₆) δ (ppm): 8.61 (1H, s), 8.60 (1H, s), 8.53 (1H, dd,J=5.0 Hz, 1.7 Hz), 8.10 (1H, brt, J=4.9 Hz), 7.82 (1H, dd, J=7.9 Hz, 1.7Hz), 7.42 (1H, dd, J=7.9 Hz,. 5.0 Hz), 7.24 (1H, s), 7.22 (1H, s), 4.55(2H, d, J=4.9 Hz), 3.94 (3H, s), 3.93 (3H, s), 3.80 (4H, m), 3.71 (4H,m).

FAB-Mass: 457 ((M+1)⁺)

EXAMPLE 574-{4-[2,2-Dicyano-1-(4-pyridylmethylamino)vinyl]-1-piperazinyl}-6,7-dimethoxyquinazoline(Compound 57)

Yield: 72%

¹H-NMR (DMSO-d₆) δ (ppm): 8.67 (1H, s), 8.58 (2H, d, J=4.6 Hz), 8.22(1H, brt, J=5.6 Hz), 7.42 (2H, d, J=4.6 Hz), 7.30 (1H, s), 7.28 (1H, s),4.59 (2H, d, J=5.6 Hz), 4.02-3.95 (10H, m), 3.75 (4H, m).

FAB-Mass: 457 ((M+1)⁺)

EXAMPLE 586,7-Dimethoxy-4-[4-(1-methylthio-2-nitrovinyl)-1-piperazinyl]quinazoline(Compound 58)

To an ethanol solution (30 mL) of6,7-dimethoxy-4-(1-piperazinyl)quinazoline described in South AfricanPatent 67 06512 (1968) (Compound (i); 6.00 g, 21.9 mmol), commerciallyavailable 1,1-bis(methylthio)-2-nitroethylene (4.27 g, 25.8 mol) wasadded, followed by stirring under heating at 50 C for 9 hours and thenheating under reflux for 2.5 hours. After the reaction solution wasallowed to stand for cooling, the solvent was evaporated and then theresulting residue was purified by silica gel column chromatography togive the target compound (2.65 g, 6.78 mmol).

Yield: 31%

¹H-NMR (CDCl₃) δ (ppm): 8.61 (1H, s), 7.20 (1H, s), 7.02 (1H, s), 6.64(1H, s), 3.96 (3H, s), 3.93 (3H, s), 3.74 (8H, m), 2.42 (3H, s),

FAB-Mass: 392 ((M+1)⁺)

EXAMPLE 596,7-Dimethoxy-4-{4-[2-nitro-1-(4-pyridylmethylamino)vinyl]-1-piperazinyl}quinazoline(Compound 59)

To a pyridine solution (10 mL) of Compound 58 produced in Example 58(730 mg, 1.87 mmol), 4-aminomethylpyridine (0.57 mL, 5.61 mmol) wasadded, followed by stirring in argon atmosphere under heating at 80° C.for 5 hours. After the reaction solution was allowed to stand forcooling, the solvent was evaporated, and the resulting residue waspurified by silica gel column chromatography to give the target compound(130 mg, 0.29 mmol).

Yield: 15%

¹H-NMR (DMSO-d₆) δ (ppm): 9.01 (1H, br), 8.57 (2H, d, J=5.9 Hz), 8.57(1H, s), 7.36 (2H, d, J=5.9 Hz), 7.24 (1H, s), 7.18 (1H, s), 6.40 (1H,s), 4.56 (2H, d, J=5.3 Hz), 3.94 (3H, s), 3.93 (3H, s), 3.76 (4H, m),3.54 (4H, m).

FAB-Mass: 452 ((M+1)⁺)

EXAMPLE 606,7-Dimethoxy-4-{4-[1-(3,4-methylenedioxybenzylamino)-2-nitrovinyl]-1-piperazinyl}quinazoline(Compound 60)

The target compound was produced in the same manner as in Example 59,except that 4-aminomethylpyridine was replaced with3,4-methylenedioxybenzylamine.

Yield: 8%

¹H-NMR (CDCl₃) δ (ppm): 9.79 (1H, br), 8.71 (1H, s), 7.29 (1H, s), 7.06(1H, s), 6.82-6.73 (3H, m), 6.56 (1H, s), 5.98 (2H, s), 4.46 (2H, d,J=5.6 Hz), 4.04 (3H, s), 4.00 (3H, s), 3.75-3.71 (4H, m), 3.44-3.41 (4H,m).

FAB-Mass: 495 ((M+1)⁺)

EXAMPLE 61N,N′-Dicyclohexyl-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamidine(Compound 61)

To an acetonitrile solution (10 mL) of Compound (i) (500 mg, 1.82 mmol),N,N′-Dicyclohexylcarbodiimide (DCC) (376 mg, 1.82 mmol) was added,followed by stirring at room temperature overnight. DCC (376 mg, 1.82mmol) was further added thereto, followed by heating under reflux for 3days, and then chloroform (10 mL) was added thereto, followed by furtherheating under reflux for 3 days. DCC (376 mg, 1.82 mmol) was furtheradded thereto, followed by refluxing for 2 days, and then the residueobtained by evaporating the solvent was purified by silica gel columnchromatography and further purified by preparative thin layerchromatography to give the target compound (73 mg, 0.15 mmol).

Yield: 8%

¹H-NMR (DMSO-d₆) δ (ppm): 8.62 (1H, s), 7.65 (1H, br), 7.28 (1H, s),7.21 (1H, s), 3.94 (3H, s), 3.94 (3H, s), 3.81 (4H, br), 3.62 (4H, br),3.32 (2H, m), 1.87-1.72 (8H, m), 1.62-1.57.(2H, m), 1.43-1.07 (10H, m).

FAB-Mass: 481 ((M+1)⁺)

EXAMPLE 624-(6,7-Dimethoxy-4-quinazolinyl)-N-tosyl-1-piperazinecarboximidicthioacid methyl ester (Compound 62)

To an isopropanol solution (20 mL) of Compound (i) (1.00 g, 3.65 mmol),commercially available N-[bis(methylthio)methylene]-p-toluenesulfonamide(1.10 g, 3.99 mmol) was added, followed by heating under reflux for 2days. After the reaction solution was allowed to stand for cooling, theprecipitated crystals were recovered by filtration and washed withisopropanol to give the target compound (1.06 g, 2.12 mmol).

Yield: 58%

¹H-NMR (CDCl₃) δ (ppm): 8.68 (1H, s), 7.83 (2H, d, J=8.2 Hz), 7.27 (1H,s), 7.27 (2H, d, J=8.2 Hz), 7.06 (1H, s), 4.03 (3H, s), 4.03-4.01 (4H,m), 3.99 (3H, s), 3.82-3.78 (4H, m) , 2.43 (3H, s) , 2.41 (3H, s).

FAB-Mass: 502 ((M+1)⁺)

EXAMPLE 634-(6,7-Dimethoxy-4-quinazolinyl)-N′-(3,4-methylenedioxybenzyl)-N-tosyl-1-piperazinecarboxamidine(Compound 63)

To a pyridine solution (5 mL) of Compound 62 produced in Example 62 (599mg, 1.20 mmol), piperonylamine (0.74 mL, 5.94 mmol) was added, followedby heating under reflux in argon atmosphere for 5 hours. After thereaction solution was allowed to stand for cooling, water and sodiumchloride were added thereto, and the thus precipitated crystals wererecovered by filtration, washed with water, dried and then purified bysilica gel column chromatography to give the target compound (248 mg,0.41 mmol).

Yield: 34%

¹H-NMR (CDCl₃) δ (ppm): 8.66 (1H, s), 7.66 (2H, d, J=8.3 Hz), 7.28-7.26(2H, m), 7.21 (2H, d, J=8.3 Hz), 7.06 (1H, s), 6.76-6.60 (3H, m), 5.98(2H, s), 4.23 (2H, d, J=5.3 Hz), 4.03 (3H, s), 3.99 (3H, s), 3.72-3.71(4H, m), 3.61-3.60 (4H, m), 2.40 (3H, s).

FAB-Mass: 605 ((M+1)⁺)

EXAMPLE 644-[4-(2,2-Dicyano-1-methylthiovinyl)-1-piperazinyl]-6,7-dimethoxyquinazoline(Compound 64)

Commercially available [bis(methylthio)methylene]-propanedinitrile (3.40g, 20.0 mmol) was added to an acetonitrile solution (50 mL) of Compound(i) (5.00 g, 18.2 mmol), and the mixture was heated under reflux for 4.5hours. After there action solution was allowed to stand for cooling, theprecipitated crystals were recovered by filtration, washed withacetonitrile, and dried to give the target compound (6.17 g, 15.6 mmol).

Yield: 85%

¹H-NMR (CDCl₃) 67 (ppm): 8.71 (1H, s), 7.29 (1H, s), 7.06 (1H, s),4.06-3.94 (4H, m), 4.04 (3H, s), 4.01 (3H, s), 3.87-3.83 (4H, m), 2.65(3H, s).

FAB-Mass: 397 ((M+1)⁺)

EXAMPLE 65N-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboximidicthioacid methyl ester (Compound 65)

To an ethanol solution (30 mL) of Compound (i) (5.00 g, 18.2 mmol),commercially available S,S′-dimethyl-N-cyanodithioimide carbonate (3.26g, purity 90%, 20.1 mmol) was added, followed by heating under refluxfor 14.5 hours. After the reaction solution was allowed to stand forcooling, the precipitated crystals were recovered by filtration, washedwith ethanol, and then dried to give the target compound (5.69 g, 15.3mmol).

Yield: 84%

¹H-NMR (CDCl₃) δ (ppm): 8.70 (1H, s), 7.28 (1H, s), 7.06 (1H, s),4.09-4.05 (4H, m), 4.04 (3H, s), 4.00 (3H, s), 3.78-3.75 (4H, m), 2.83(3H, s).

FAB-Mass: 373 ((M+1)⁺)

EXAMPLE 66N-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboximidic acidethyl ester (Compound 66)

The target compound (66.7 mg, 0.18 mmol) was produced together withCompound 31 under the reaction conditions of Example 31.

Yield: 17%

¹H-NMR (CDCl₃) δ (ppm): 8.70 (1H, s), 7.28 (1H, s), 7.06 (1H, s), 4.50(2H, q, J=7.3 Hz), 4.04 (3H, s), 4.00 (3H, s), 3.95-3.92 (4H, m),3.75-3.71 (4H, m), 1.38 (3H, t, J=7.3 Hz).

FAB-Mass: 371 ((M+1)⁺)

EXAMPLE 67N-Cyano-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboximidic acidphenyl ester (Compound 67)

To an isopropanol solution (25 mL) of Compound (i) (1.00 g,3.65 mmol),commercially available cyanocarbonimic acid phenyl ester (0.96 g, 4.03mmol) was added, followed by heating under reflux for 12 hours. Afterthe reaction solution was allowed to stand for cooling, the precipitatedcrystals were recovered by filtration and washed with isopropanol togive the target compound (0.70 g, 1.67 mmol).

Yield: 46%

¹H-NMR (CDCl₃) δ (ppm): 8.72 (1H, s), 7.46-7.40 (2H, m), 7.31-7.25 (2H,m), 7.13 (2H, d, J=8.6 Hz), 7.07 (1H, s), 4.04 (3H, s), 4.00 (3H, s),3.96 (4H, m), 3.79-3.76 (4H, m).

FAB-Mass: 419 ((M+1)⁺)

EXAMPLE 68N′-Cyano-N-(3,4-dimethoxyphenyl)-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamidine(Compound 68)

To an acetonitrile solution (15 mL) ofN-(3,4-dimethoxyphenyl)-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinethiocarboxamide(499 mg, 1.07 mmol) described in WO 98/14431, DCC (4397 mg, 2.13 mmol),N,N-diisopropylethylamine (Hünig base) (0.19 mL, 1.09 mmol) andcyanamide (224 mg, 5.32 mmol) were added, followed by heating underreflux in argon atmosphere for 2 days. DCC (439 mg, 2.13 mmol), Hünigbase (0.19 mL, 1.09 mmol) and cyanamide (224 mg, 5.32 mmol) were furtheradded thereto, followed by heating under reflux for 2 days. After thereaction solution was concentrated, the resulting residue was purifiedby silica gel column chromatography to give the target compound (167 mg,0.35 mmol).

Yield: 33%

¹H-NMR (CDCl₃) δ (ppm): 8.66 (1H, s), 7.40 (1H, brs), 7.26 (1H, s), 7.02(1H, s), 6.83 (1H, d, J=9.2 Hz), 6.68-6.64 (2H, m), 4.02 (3H, s), 3.97(3H, s), 3.87 (3H, s), 3.87 (3H, s), 3.64-3.58 (8H, m).

FAB-Mass: 478 ((M+1)⁺)

EXAMPLE 69N-(4-Phenoxyphenyl)-4-(4-pyrazolo[3,4-d]pyrimidinyl)-1-piperazinecarboxamide(Compound 69)

The target compound was produced in the same manner as in Example 2,except that 4-(6-purinyl)-1-piperazinecarboxylic acid tert-butyl esterwas replaced with 4-(4-pyrazolo[3,4-d]pyrimidinyl)-1-piperazinecarboxylic acid tert-butyl ester produced in ReferenceExample 10, and that 4-nitrophenyl isocyanate was replaced with4-phenoxyphenyl isocyanate.

Yield: 48%

¹H-NMR (CDCl₃) δ (ppm): 8.43 (1H, s), 8.04 (1H, s), 7.36-7.29 (4H, m),7.09 (1H, m), 7.01-6.97 (4H, m), 6.32 (1H, brs), 4.20-4.16 (4H, m),3.82-3.80 (4H, m).

FAB-Mass: 41.6 ((M+1)⁺)

EXAMPLE 70 N-(4-Phenoxyphenyl)-4-(6-hydroxy-4-imidazo[4,5-d]-pyrimidinyl)-1-piperazinecarboxamide(Compound 70)

The target compound was produced in the same manner as in Example 2,except that 4-(6-purinyl)-1-piperazinecarboxylic acid tert-butyl esterwas replaced with 4-(6-hydroxy-4-imidazo[4, 5-d]pyrimidinyl)-1-piperazinecarboxylic acid tert-butyl ester produced in ReferenceExample 11, and that 4-nitrophenyl isocyanate was replaced with4-phenoxyphenyl isocyanate.

Yield: 52%

¹H-NMR (DMSO-d₆) δ (ppm): 11. 50 (1H, br), 10. 85 (1H, br), 8. 64(1H,brs), 8.13 (1H, s), 7.49 (2H, d, J=8.9 Hz), 7.39-7.33 (2H, m), 7.08 (1H,m), 6..96-6.93 (4H, m), 3.57 (8H, m).

FAB-Mass: 432 ((M+1)⁺)

Reference Example 14-[N-(4-Phenoxyphenyl)carbamoyl]-1-piperazinecarboxylic acid tert-butylester

To a methylene chloride solution (25 mL) ofN-tert-butoxycarbonylpiperazine (2.50 g, 13.4 mmol), 4-phenoxyphenylisocyanate (2.83 mL, 13.4 mmol) was added, followed by stirring at roomtemperature overnight. Methanol was added to the reaction solution, andthe solvent was evaporated to give the target compound (5.71 g, 14.4mmol).

Yield: quantitative

¹H-NMR (CDCl₃) δ (ppm): 7.35-7.26 (4H, m), 7.07 (1H, m), 6.99-6.95 (4H,m), 6.35 (1H, brs), 3.49 (8H, m), 1.48 (9H, s).

FAB-Mass: 398 ((M+1)⁺)

Reference Example 2 4-(2-Amino-6-purinyl)-1-piperazinecarboxylic acidtert-butyl ester

To a dimethylformamide suspension (20 mL) of commercially available2-amino-6-chloropurine (3.00 g, 17.7 mmol), triethylamine (12.3 mL, 88.2mmol) and N-tert-butoxycarbonylpiperazine (3.62 g, 19.4mmol) were added,followed by stirring at room temperature for 4 hours and then stirringunder heating at 60° C. for 6 hours. After the reaction solution wasallowed to stand for cooling, it was poured into water, sodium chloridewas added thereto, and then the precipitated crystals were recovered byfiltration, washed with water, and dried to give the target compound(2.50 g, 7.84 mmol).

Yield: 44%

¹H-NMR (DMSO-d₆) δ (ppm): 12.20 (1H, br), 7.70 (1H, s), 5.77 (2H, brs),4.11 (4H, m), 3.43-3.39 (4H, m), 1.43 (9H, s).

FAB-Mass: 320 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1695, 1610,1568, 1487,1421,1261, 1171,1009.

Reference Example 3 6-(1-Piperazinyl)purine

To an isopropanol solution (50 mL) of piperazine (5.57 g, 64.7 mmol),6-chloropurine (1.00 g, 6.47 mmol) was added, followed by stirring atroom temperature for 1.5 hours and then heating under reflux for 2.5hours. The reaction solution was concentrated, saturated brine was addedthereto, the mixture was extracted with chloroform and THF in thatorder, the extract was dried over anhydrous sodium sulfate, and then thesolvent was evaporated to give the target compound. Thereafter, thewater layer after extraction was allowed to stand, and then theprecipitated crystals were recovered by filtration to give the targetcompound (1.07 g in total, 5.25 mmol).

Yield: 81%

Reference Example 44-(5-Carbamoyl-1,3-dimethyl-4-1H-pyrazolo[3,4-b]pyridyl)-1-piperazinecarboxylicacid tert-butyl ester

The target compound was produced in the same manner as in ReferenceExample 2, except that 2-amino-6-chloropurine was replaced withcommercially available4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide.

Yield: 97%

¹H-NMR (CDCl₃) δ (ppm): 8.45 (1H, s), 6.56 (1H, br), 6.39 (1H, br), 4.01(3H, s), 3.64-3.60 (4H, m), 3.33-3.29 (4H, m), 2.67 (3H, s), 1.48 (9H,s).

FAB-Mass: 375 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1672, 1576, 1431, 1367, 1255, 1176.

Reference Example 51-Methyl-4-(1-piperazinyl)-1H-pyrazolo[3,4-d]pyrimidine

According to the method described in J. Org. Chem., 21: 1240-1256(1956), 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine was derived from4-hydroxy-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (1.20 g, 8.03 mmol). Tothis partially purified product, an isopropanol solution (50 mL) ofpiperazine (5.55 g, 64.4 mmol) was added, followed by stirring at roomtemperature for 1 hour and then heating under reflux for 1 hour. Thereaction solution was concentrated, saturated brine was added thereto,the mixture was extracted with chloroform, the extract was washed withsaturated brine and dried over anhydrous sodium sulfate, and then thesolvent was evaporated to give the target compound (1.44 g, 6.61 mmol).

Yield: 83%

Reference Example 61-Phenyl-4-(1-piperazinyl)-1H-pyrazolo[3,4-d]pyrimidine

To an isopropanol solution (10 mL) of piperazine (3.74 g, 43.4 mmol),4-chloro-1-phenylpyrazolo[3,4-d]pyrimidine (100 g, 4.34 mmol) describedin J. Org. Chem., 21: 1240-1256 (1956) was added, followed by heatingunder reflux for 6 hours. The reaction solution was concentrated,saturated brine was added thereto, the mixture was extracted withchloroform, the extract was washed with saturated brine and dried overanhydrous sodium sulfate, and then the solvent was evaporated to givethe target compound (1.07 g, 3.82 mmol).

Yield: 88%

¹H-NMR (CDCl₃+DMSO-d₆) δ (ppm): 8.43 (1H, s), 8.15-8.11 (3H, m),7.55-7.49 (2H, m), 7.34 (1H, m), 4.02-3.99 (4H, m), 3.07-3.03 (4H, m).

FAB-Mass: 281 ((M+1)⁺)

Reference Example 74-(1-Piperazinyl)-5,6-tetramethylenethieno[2,3-d]pyrimidine

The target compound was produced in the same manner as in ReferenceExample 6, except that 4-chloro-1-phenylpyrazolo[3,4-d]pyrimidine wasreplaced with 4-chloro-5,6-tetramethylenethieno[2,3-d]pyrimidinedescribed in Heterocycles, 42: 691-699 (1996).

Yield: 74%

¹H-NMR (DMSO-d₆) δ (ppm): 8.46 (1H, s), 3.35 (4H, m), 3.26-3.24 (4H, m),2.85 (4H, m), 1.88-1.86 (2H, m), 1.75-1.73 (2H, m).

FAB-Mass: 275 ((M+1)⁺)

Reference Example 84-(4-Pyrido[2,3-d]pyrimidinyl)-1-piperazinecarboxylic acid tert-butylester

To a dimethylformamide solution (10 ml) of4-mercaptopyrido[2,3-d]pyrimidine (742 mg, 4.55 mmol) described in J.Am. Chem. Soc., 77: 2256-2260 (1955), potassium carbonate(755 mg, 5.47mmol) and methyl iodide (0.34 mL, 5.47 mmol) were added, followed bystirring in argon atmosphere at room temperature overnight.Triethylamine (3.17 ml, 22.7 mmol) and N-tert-butoxycarbonylpiperazine(1.67 g, 8.97 mmol) were added thereto, followed by stirring at roomtemperature overnight, and then a N-tert-butoxycarbonylpiperazine (0.90g, 4.83 mmol) was further added thereto, followed by stirring for 3.5hours under heating at 110° C. The reaction solution was allowed tostand for cooling, water was added thereto, the mixture was extractedwith methylene chloride, the extract was washed with saturated brine anddried over anhydrous sodium sulfate, then the solvent was evaporated andthe resulting residue was purified by silica gel column chromatographyto give the target compound (1.05 g, 3.33 mmol).

Yield: 73%

¹H-NMR (CDCl₃) δ (ppm): 9.05 (1H, dd, J=4.3 Hz, 2.0 Hz), 8.86 (1H, s),8.26 (1H, dd, J=8.2 Hz, 2.0 Hz), 7.40 (1H, dd, J=8.2 Hz, 4.3 Hz),3.86-3.82 (4H, m), 3.68-3.65 (4H, m), 1.50 (9H, s).

FAB-Mass: 316 ((M+1)⁺)

IR (KBr tablet method) ν (cm⁻¹): 1686, 1560, 1497, 1421, 1365, 1333,1244, 1163, 1005, 808.

Reference Example 94-(6-Fluoro-4-pyrido[3,4-d]pyrimidinyl)-1-piperazinecarboxylic acidtert-butyl ester

According to the method described in J. Med. Chem., 39:1823-1835 (1996),4-chloro-6-fluoropyrido[3,4-d]pyrimidine was derived from6-fluoropyrido[3,4-d]pyrimidine-4(3H)-one (1.48 g, 8.96 mmol).Triethylamine (3.75 mL, 26.9 mmol) and N-tert-butoxycarbonylpiperazine(2.00 g, 10.7 mmol) were added to a methylene chloride solution (25 mL)of this partially purified product, followed by stirring at roomtemperature overnight. Saturated brine was added to the reactionsolution, the mixture ma was extracted with chloroform, the extract wasdried over anhydrous sodium sulfate, then the solvent was evaporated andthe resulting residue was purified by silica gel column chromatographyto give the target compound (1.73 g, 5.20 mmol).

Yield: 58%

¹H-NMR (CDCl₃) δ (ppm): 9.03 (1H, s), 8.76 (1H, s), 7.28 (1H, d, J=2.0Hz), 3.87-3.83 (4H, m), 3.69-3.65 (4H, m), 1.51 (9H, s).

FAB-Mass: 334 ((M+1)⁺)

Reference Example 104-(4-Pyrazolo[3,4-d]pyrimidinyl)-1-piperazinecarboxylic acid tert-butylester

A dibromomethane suspension (5 mL) of commercially available4-aminopyrazolo[3,4-d]pyrimidine (420.8 mg, 3.11 mmol) was heated to 80°C., and isoamyl nitrite (0.43 mL, 3.20 mmol) was added thereto, followedby stirring at the same temperature for 3 hours. Isoamyl nitrite (0.43mL, 3.20 mmol) was further added thereto, followed by heating underreflux for 3.5 hours, and then the insoluble matter was removed byfiltration. The filtrate was concentrated, the resulting residue wasdissolved in dimethylformamide (5 mL), and then triethylamine (2.00 mL,14.3 mmol) and N-tert-butoxycarbonylpiperazine (1.00 g, 5.37 mmol) wereadded thereto, followed by stirring at room temperature overnight. Afterthe reaction solution was concentrated, the resulting residue waspurified by silica gel column chromatography to give the target compound(20.4 mg, 0.07 mmol).

Yield: 2%

¹H-NMR (CDCl₃) δ (ppm): 8.43 (1H, s), 8.03 (1H, s), 4.05-4.02 (4H, m),3.68-3.64 (4H, m), 1.51 (9H, s).

FAB-Mass: 305 ((M+1)⁺)

Reference Example 114-(6-Hydroxy-4-imidazo[4,5-d]pyrimidinyl)-1-piperazinecarboxylic acidtert-butyl ester

(1) To a methylene chloride solution (50 mL) saturated with ammonia,commercially available 4,6-dichloro-5-nitropyrimidine (1.00 g, 5.44mmol) was added, followed by stirring at room temperature for 1 hour.The reaction solution was concentrated, the resulting residue wasdissolved in dimethylformamide (10 mL), and thenN-tert-butoxycarbonylpiperazine (1.15 g, 6.17 mmol) and triethylamine(3.59 mL, 25.8 mmol) were added thereto, followed by stirring underheating at 80° C. for 4 hours. After the reaction solution was allowedto stand for cooling, it was poured into water, sodium chloride wasadded thereto, and the precipitated crystals were recovered byfiltration, washed with water, and dried to give4-(6-amino-5-nitro-4-pyrimidinyl)-1-piperazinecarboxylic acid tert-butylester (888 mg, 2.74 mmol).

Yield: 50%

¹H-NMR (DMSO-d₆) δ (ppm): 8.47-8.42 (2H, br), 7.99 (1H, s), 3.45 (8H,m), 1.42 (9H, s).

FAB-Mass: 325 ((M+1)⁺)

(2) To an ethanol solution (10 mL) of the compound produced in (1) (888mg, 2.74 mmol), 10% palladium-carbon (200 mg, 50% aqueous) was addedthereto, followed by stirring in a hydrogen stream at room temperaturefor 2 hours. Chloroform was added to the reaction solution, the catalystwas removed by filtration using a filter aid, and then the filtrate wasconcentrated under reduced pressure. The resulting residue was dissolvedin dimethylformamide (10 mL), and triethylamine (1.91 mL, 13.7 mmol) and1,1′-carbonyldiimidazole (888 mg, 5.48 mmol) were added thereto,followed by stirring under heating at 80° C. for 4.5 hours. After thereaction solution was allowed to stand for cooling, it was poured intowater, sodium chloride was. added thereto, and the precipitated crystalswere recovered by filtration, washed with water, and dried to give thetarget compound (161 mg, 0.50 mmol).

Yield: 18%

¹H-NMR (DMSO-d₆) δ (ppm): 11.49 (1H, br), 10.83 (1H, br), 8.10 (1H, s),3.50-3.48 (4H, m), 3.43-3.42 (4H, m), 1.42 (9H, s).

FAB-Mass: 321 ((M+1)⁺)

Formulation Example 1

Tablets

Tablets comprising the following composition are prepared in a usualmethod.

Compound 5 100 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2mg Magnesium stearate 1 mg Tar dye trace amount

Formulation Example 2

Powders

Powders comprising the following composition are prepared in a usualmethod.

Compound 1 150 mg Lactose 280 mg

Formulation Example 3

Syrups

Syrups comprising the following composition are prepared in a usualmethod.

Compound 41 100 mg Purified sucrose 40 g Ethyl p-hydroxybenzoate 40 mgPropyl p-hydroxybenzoate 10 mg Strawberry flavor 0.1 cc

The total volume is adjusted to 100 cc by adding water.

Industrial Applicability

According to the present invention, nitrogen-containing heterocycliccompounds or pharmaceutically acceptable salts thereof can be provided,which are useful for the prevention or treatment of cell proliferativediseases such as arteriosclerosis, vascular re-obstruction disease,cancers, glomerulonephritis and the like, by inhibiting abnormal cellproliferation and wandering through the inhibition of phosphorylation ofPDGF receptors.

What is claimed is:
 1. A nitrogen-containing heterocyclic compound represented by formula (I):

wherein W represents 1,4-piperazinediyl or 1,4-homopiperazinediyl in which carbon atoms on the ring may be substituted with 1 to 4 alkyl groups which are the same or different; U represents NR¹R² (wherein R¹ represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic alkyl group (said alicyclic alkyl group is selected from the group consisting of monocyclic groups having from 3 to 12 carbon atoms, pinanyl, 1,7,7-trimethylbicyclo[2.2.1]heptyl, adamantyl, hexahydro-4,7-methano-1H-indenyl and 4-hexylbicyclo[2.2.2]octyl), an optionally substituted alicyclic heterocyclic group selected from the group consisting of tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl and thiomorpholinyl, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group; and R² represents a hydrogen atom, a substituted alkyl group, a substituted or unsubstituted alicyclic alkyl group (said alicyclic alkyl group is selected from the group consisting of monocyclic groups having from 3 to 12 carbon atoms, pinanyl, 1,7,7-trimethylbicyclo[2.2.1]heptyl, adamantyl, hexahydro-4,7-methano-1H-indenyl and 4-hexylbicyclo[2.2.2]octyl), an optionally substituted alicyclic heterocyclic group selected from the group consisting of tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl and thiomorpholinyl, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroarylalkyl group, CQR^(1A) (wherein Q represents an oxygen atom or a sulfur atom; and R^(1A) has the same meaning as R¹), or SO₂R³ (wherein R³ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic alkyl group (said alicyclic alkyl group is selected from the group consisting of monocyclic groups having from 3 to 12 carbon atoms, pinanyl, 1,7,7-trimethylbicyclo[2.2.1]heptyl, adamantyl, hexahydro-4.7-methano-1H-indenyl and 4-hexylbicyclo[2.2.2]octyl), an optionally substituted alicyclic heterocyclic group selected from the group consisting of tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl and thiomorpholinyl, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group)), OR⁴ (wherein R⁴ has the same meaning as R³), or SR⁵ (wherein R⁵ has the same meaning as R³); V represents an oxygen atom, a sulfur atom, N—R⁶ (wherein R⁶ has the same meaning as R¹ or represents a cyano group, a hydroxyl group, a nitro group, a carbamoyl group, COOR^(3A) (wherein R^(3A) has the same meaning as R³), CQ^(A)R^(1B) (wherein Q^(A) has the same meaning as Q, and R^(1B) has the same meaning as R¹), or SO₂R^(3B) (wherein R^(3B) has the same meaning as R³)), or CR⁷R⁸ (wherein R⁷ and R⁸ are the same or different and each represents a hydrogen atom, a cyano group, a nitro group, COOR^(3C) (wherein R^(3C) has the same meaning as R³), or SO₂R^(3D) (wherein R^(3D) has the same meaning as R³)), with the proviso that, when R¹ is hydrogen, R⁶ and R² may be exchanged, V may represent N—R², or —R⁶, and when U is OR⁴ or SR⁵, V represents N—R⁶ or CR⁷R⁸, at least one of X, Y and Z represents a nitrogen atom, and the others are the same or different, and each represents a nitrogen atom or C—R^(A) <wherein R^(A) has the same meaning as R¹, or represents a halogen atom, a cyano group, a nitro group, NR⁹R¹⁰ {wherein R⁹ and R¹⁰ are the same or different, and each has the same meaning as R¹, or represents SO₂R^(3E) (wherein R^(3E) has the same meaning as R³) or CQ^(B)R¹¹ (wherein Q^(B) has the same meaning as Q; and R¹¹ has the same meaning as R¹, or represents OR^(3F) (wherein R^(3F) has the same meaning as R³) or NR^(1C)R^(1D) (wherein R^(1C) and R^(1D) are the same or different, and each has the same meaning as R¹, or R^(1C) and R^(1D) are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group)), or R⁹ and R¹⁰ are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group}, CQ^(C)R^(11A) (wherein Q^(C) has the same meaning as Q; and R^(11A) has the same meaning as R¹¹), OR¹² {wherein R¹² has the same meaning as R¹, or represents CQ^(D)R¹³ (wherein Q^(D) has the same meaning as Q; and R¹³ has the same meaning as R¹, or represents OR^(3G) (wherein R^(3G) has the same meaning as R³), SR^(3H) (wherein R^(3H) has the same meaning as R³), or NR^(1E)R^(1F) (wherein R^(1E) and R^(1F) are the same or different, and each has the same meaning as R¹, or R^(1E) and R^(1F) are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group)), or SO₂R^(3I) (wherein R^(3I) has the same meaning as R³)}, SR^(1G) (wherein R^(1G) has the same meaning as R¹), SOR^(3J) (wherein R^(3J) has the same meaning as R³) or SO₂R¹⁴ (wherein R¹⁴ has the same meaning as R³, or represents OR^(1H) (wherein R^(1H) has the same meaning as R¹) or NR^(1I)R^(1J) (wherein R^(1I) and R^(1J) are the same or different, and each has the same meaning as R¹, or R^(1I) and R^(1J) are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group)) >, and (1) when V represents N—R⁶ or CR⁷R⁸, and U represents NR¹R², OR⁴, or SR⁵, D¹, D², D³ and D⁴ each independently represent C—R^(B) (wherein R^(B) has the same meaning as R^(A)), a nitrogen atom, an oxygen atom, or a sulfur atom; or optional adjoining two among D¹ to D⁴ may be combined to represent a nitrogen atom, N—R^(2A) (wherein R^(2A) has the same meaning as R², or represents an alkyl group or CQ^(E)NHR^(3K) (wherein Q^(E) has the same meaning as Q; and R^(3K) has the same meaning as R³)), an oxygen atom, or a sulfur atom, and the remains among D¹ to D⁴ may represent C—R^(B′) (wherein R^(B′) has the same meaning as R^(A)), N—R^(2A) (wherein R^(2A) has the same meaning as R^(2A), or a nitrogen atom; and in these two cases, the optional adjoining two selected from D¹ to D⁴ may represent C—R^(B″) (wherein two R^(B″)s, together with the two adjoining carbon atoms, represent an optionally substituted alicyclic alkene selected from the group consisting of cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and cyclododecene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted imidazol-2-one, substituted or unsubstituted imidazole-2-thione, substituted or unsubstituted triazole, substituted or unsubstituted furan, substituted or unsubstituted 1,3-dioxole, substituted or unsubstituted 1,4-dioxene, substituted or unsubstituted thiophene, substituted or unsubstituted oxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted triazine, substituted or unsubstituted tetrazine, or substituted or unsubstituted benzene), and (2) when V represents an oxygen atom or a sulfur atom, and U represents NR¹R² (2-1) at least one of D¹ to D⁴ represents a nitrogen atom, an oxygen atom or a sulfur atom; optional adjoining two among D¹ to D⁴ are combined to represent a nitrogen atom, N—R^(2B) (wherein R^(2B) has the same meaning as R²), or an oxygen atom; or D² and D³ are combined to represent a sulfur atom; and in these three cases, the remains among D¹ to D⁴ represent a nitrogen atom, N—R^(2B′) (wherein R^(2B′) has the same meaning as R²), an oxygen atom, a sulfur atom, or C—R^(C) (wherein the R^(C)s each independently have the same meaning as R^(A), or optional two R^(C)s′ adjoining adjacent carbon atoms, together with the two adjoining carbon atoms, may represent an optionally substituted alicyclic alkene selected from the group consisting of cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and cyclododecene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted imidazol-2-one, substituted or unsubstituted imidazole-2-thione, substituted or unsubstituted triazole, substituted or unsubstituted furan, substituted or unsubstituted 1,3-dioxole, substituted or unsubstituted 1,4-dioxene, substituted or unsubstituted oxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiophene, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted triazine, substituted or unsubstituted tetrazine, or substituted or unsubstituted benzene), (2-2) D¹ and D² are combined to represent a sulfur atom; D³ represents C—R^(C′) (wherein R^(C′) has the same meaning as R^(A)); and D⁴ represents a nitrogen atom, or D³ and D⁴ represent C—R^(C″) (wherein R^(C″)s, together with two adjoining carbon atoms, represent an optionally substituted alicyclic alkene selected from the group consisting of cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and cyclododecene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted imidazol-2-one, substituted or unsubstituted imidazole-2-thione, substituted or unsubstituted triazole, substituted or unsubstituted furan, substituted or unsubstituted 1,3-dioxole, substituted or unsubstituted 1,4-dioxene, substituted or unsubstituted oxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiophene, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted triazine, substituted or unsubstituted tetrazine, or substituted or unsubstituted benzene), (2-3) D³ and D⁴ are combined to represent a sulfur atom; D² represents C—R^(C″) (wherein R^(C′″) has the same meaning as R^(A)); and D¹ represents a nitrogen atom, or D¹ and D² represent C—R^(C″″) (wherein R^(C″″) has the same meaning as R^(C″)), or (2-4) D¹, D², D³ and D⁴ represent C—R^(D) (wherein in R^(D)s, optional two R^(D)s′ adjoining adjacent carbon atoms, together with the two adjoining carbon atoms, represent an optionally substituted alicyclic alkene selected from the group consisting of cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and cyclododecene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted isothiazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted triazine, or substituted or unsubstituted tetrazine, and each of the remaining R^(D)s independently represents the same meaning as R^(A)), or a pharmaceutically acceptable salt thereof.
 2. The nitrogen-containing heterocyclic compound according to claim 1, wherein W represents 1,4-piperazinediyl, or a pharmaceutically acceptable salt thereof.
 3. The nitrogen-containing heterocyclic compound according to claim 2, wherein at least one of X and Z represents a nitrogen atom; and Y represents C—R^(A) or a pharmaceutically acceptable salt thereof.
 4. The nitrogen-containing heterocyclic compound according to claim 3, wherein X and Z each represent a nitrogen atom; and R^(A) represents a hydrogen atom or NR⁹R¹⁰, or a pharmaceutically acceptable salt thereof.
 5. The nitrogen-containing heterocyclic compound according to claim 4, wherein U represents NR¹R², or a pharmaceutically acceptable salt thereof.
 6. The nitrogen-containing heterocyclic compound according to claim 5, wherein R¹ represents a hydrogen atom; and R² represents a hydrogen atom, a substituted alkyl group, a substituted or unsubstituted alicyclic alkyl group (said alicyclic alkyl group is selected from the group consisting of monocyclic groups having from 3 to 12 carbon atoms, pinanyl, 1,7,7-trimethylbicyclo[2.2.1]heptyl, adamantyl, hexahydro-4,7-methano-1H-indenyl and 4-hexylbicyclo[2.2.2]octyl), an optionally substituted alicyclic heterocyclic group selected from the group consisting of tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl and thiomorpholinyl, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group, or a pharmaceutically acceptable salt thereof.
 7. The nitrogen-containing heterocyclic compound according to claim 6, wherein R² represents a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group, or a pharmaceutically acceptable salt thereof.
 8. The nitrogen-containing heterocyclic compound according to claim 7, wherein V represents N—R⁶; and 1) D¹ and D² are combined to represent N—R^(2A); and D³ and D⁴ each independently represent C—R^(B′), 2) D¹ and D² each independently represent C—R^(B′); and D³ and D⁴ are combined to represent N—R^(2A), 3) D¹ and D⁴ each independently represent C—R^(B′); and D² and D³ are combined to represent N—R^(2A), 4) D¹ represents C—R^(B′); D² and D³ are combined to represent a nitrogen atom; and D⁴ represents N—R^(2A′), 5) D⁴ represents C—R^(B′); D² and D³ are combined to represent a nitrogen atom; and D¹ represents N—R^(2A′), 6) D¹ and D² are combined to represent N—R^(2A); D³ represents C—R^(B′); and D⁴ represents a nitrogen atom, 7) D¹ and D² are combined to represent a nitrogen atom; D³ represents C—R^(B′); and D⁴ represents N—R^(2A), 8) D¹, D² and D³ each independently represent C—R^(B); and D⁴ represents a nitrogen atom, 9) D¹, D² and D⁴ each independently represent C—R^(B); and D³ represents a nitrogen atom, 10) D¹, D³ and D⁴ each independently represent C—R^(B); and D² represents a nitrogen atom, 11) D¹, D³ and D⁴ each independently represent C—R^(B); and D¹ represents a nitrogen atom, 12) D¹ and D³ represent nitrogen atoms; and D² and D⁴ each independently represent C—R^(B), 13) D¹ and D³ each independently represent C—R^(B); and D² and D⁴ represent nitrogen atoms, 14) D¹ and D² each independently represent C—R^(B); and D³ and D⁴ represent nitrogen atoms, 15) D¹ and D⁴ each independently represent C—R^(B); and D² and D³ represent nitrogen atoms, 16) D³ and D⁴ each independently represent C—R^(B); and D¹ and D² represent nitrogen atoms, 17) D² and D³ each independently represent C—R^(B); and D¹ and D⁴ represent nitrogen atoms, 18) D¹, D², D³ and D⁴ each independently represent C—R^(B), 19) D¹ and D² each independently represent C—R^(B′); and D³ and D⁴ are combined to represent a sulfur atom, 20) D¹ and D⁴ each independently represent C—R^(B′); and D² and D³ are combined to represent a sulfur atom, or 21) D³ and D⁴ each independently represent C—R^(B′); and D¹ and D² are combined to represent a sulfur atom, or a pharmaceutically acceptable salt thereof.
 9. The nitrogen-containing heterocyclic compound according to claim 7, wherein V represents an oxygen atom or a sulfur atom; and 1) D¹ and D² are combined to represent N—R^(2B); and D³ and D⁴ each independently represent C—R^(C), 2) D¹ and D² each independently represent C—R^(C); and D³ and D⁴ are combined to represent N—R^(2B), 3) D¹ and D⁴ each independently represent C—R^(C); and D² and D³ are combined to represent N—R^(2B), 4) D¹ represents C—R^(C); D² and D³ are combined to represent a nitrogen atom; and D⁴ represents N—R^(2B′), 5) D⁴ represents C—R^(C); D² and D³ are combined to represent a nitrogen atom; and D¹ represents N—R^(2B′), 6) D¹ and D² are combined to represent N—R^(2B); D³ represents C—R^(C); and D⁴ represents a nitrogen atom, 7) D¹ and D² are combined to represent a nitrogen atom; D³ represents C—R^(C); and D⁴ represents N—R^(2B′), 8) D¹, D² and D³ each independently represent C—R^(C); and D⁴ represents a nitrogen atom, 9) D¹, D² and D⁴ each independently represent C—R^(C); and D³ represents a nitrogen atom, 10) D¹, D³ and D⁴ each independently represent C—R^(C); and D² represents a nitrogen atom, 11) D², D³ and D⁴ each independently represent C—R^(C); and D¹ represents a nitrogen atom, 12) D¹ and D³ represent nitrogen atoms; and D² and D⁴ each independently represent C—R^(C), 13) D¹ and D³ each independently represent C—R^(C); and D² and D⁴ are nitrogen atoms, 14) D¹ and D² each independently represent C—R^(C); and D³ and D⁴ are nitrogen atoms, 15) D¹ and D⁴ each independently represent C—R^(C); and D² and D³ are nitrogen atoms, 16) D³ and D⁴ each independently represent C—R^(C); and D¹ and D² are nitrogen atoms, 17) D² and D³ each independently represent C—R^(C); and D¹ and D⁴ are nitrogen atoms, 18) D¹, D², D³ and D⁴ each independently represent C—R^(D), 19) D¹ and D² each independently represent C—R^(C″″); and D² and D³ are combined to represent a sulfur atom, 20) D¹ and D⁴ each independently represent C—R^(C); and D² and D³ are combined to represent a sulfur atom, or 21) D³ and D⁴ each independently represent C—R^(C″); and D¹ and D² are combined to represent a sulfur atom, or a pharmaceutically acceptable salt thereof.
 10. The nitrogen-containing heterocyclic compound according to claim 8, wherein R⁶ represents CN; and 1) D¹ and D² are combined to represent a nitrogen atom; D³ represents C—R^(B′); and D⁴ represents N—R^(2A′), 2) D¹, D² and D⁴ each independently represent C—R^(B); and D³ represents a nitrogen atom, or 3) D¹, D², D³ and D⁴ each independently represent C—R^(B), or a pharmaceutically acceptable salt thereof.
 11. The nitrogen-containing heterocyclic compound according to claim 9, 1) D¹ and D² are combined to represent a nitrogen atom; D³ represents C—R^(C); and D⁴ represents N—R^(2B′), 2) D¹, D² and D⁴ each independently represent C—R^(C); and D¹ represents a nitrogen atom, or 3) D¹, D², D³ and D⁴ each independently represent C—R^(D), or a pharmaceutically acceptable salt thereof.
 12. The nitrogen-containing heterocyclic compound according to claim 7, wherein V represents an oxygen atom or a sulfur atom; D¹, D², D³ and D⁴ represent C—R^(D); and optional two R^(D)s^(′) adjoining adjacent carbon atoms, together with the two adjoining carbon atoms, represent substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, or substituted or unsubstituted pyrazine, or a pharmaceutically acceptable salt thereof.
 13. A nitrogen-containing heterocyclic compound represented by formula (I):

wherein W represents 1,4-piperazinediyl or 1,4-homopiperazinediyl in which carbon atoms on the ring may be substituted with 1 to 4 alkyl groups which are the same or different; U represents NR¹R² (wherein R¹ represents a hydrogen atom a substituted or unsubstituted alkyl group, a substituted or unsubstituted group being selected from monocyclic groups having from 3 to 12 carbon atoms, pinanyl, 1,7,7-trimethylbicyclo[2.2.1]heptyl, adamantly, hexahydro-4,7-methano-1H-indenyl and 4-hexylbicyclo[2.2.2]octyl, an optionally substituted heterocyclic group selected from the group consisting of tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl and thiomorpholinyl, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group; and R² represents a hydrogen atom, a substituted alkyl group, a substituted or unsubstituted group being selected from monocyclic groups having from 3 to 12 carbon atoms, pinanyl, 1,7,7-trimethylbicyclo[2.2.1]heptyl, adamantly, hexahydro-4,7-methano-1H-indenyl and 4-hexylbicyclo[2.2.2]octyl, an optionally substituted heterocyclic group selected from the group consisting of tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl and thiomorpholinyl, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroarylalkyl group, CQR^(1A) (wherein Q represents an oxygen atom or a sulfur atom; and R^(1A) has the same meaning as R¹), or SO₂R³ (wherein R³ represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted group (said group being selected from monocyclic groups having from 3 to 12 carbon atoms, pinanyl, 1,7,7-trimethylbicyclo[2.2.1]heptyl, adamantly, hexahydro-4,7-methano-1H-indenyl and 4-hexybicyclo[2.2.2]octyl), an optionally substituted heterocyclic group selected from the group consisting of tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl and thiomorpholinyl, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group)), OR⁴ (wherein R⁴ has the same meaning as R³), or SR⁵ (wherein R⁵ has the same meaning as R³); V represents an oxygen atom, a sulfur atom, N—R⁶ (wherein R⁶ has the same meaning as R¹ or represents a cyano group, a hydroxyl group, a nitro group, a carbamoyl group, COOR^(3A) (wherein R^(3A) has the same meaning as R³), CQ^(A)R^(1B) (wherein Q^(A) has the same meaning as Q, and R^(1B) has the same meaning as R¹), or SO₂R^(3B) (wherein R^(3B) has the same meaning as R³)), or CR⁷R⁸ (wherein R⁷ and R⁸ are the same or different and each represents a hydrogen atom, a cyano group, a nitro group, COOR^(3C) (wherein R^(3C) has the same meaning as R³), or SO₂R^(3D) (wherein R^(3D) has the same meaning as R³)), with the proviso that, when R¹ is hydrogen, R⁶ and R² may be exchanged, V may represent N—R², or N—R⁶, and when U is OR⁴ or SR⁵, V represents N—R⁶ or CR⁷R⁸, at least one of X, Y and Z represents a nitrogen atom, and the others are the same or different, and each represents a nitrogen atom or C—R^(A) <wherein R^(A) has the same meaning as R¹, or represents a halogen atom, a cyano group, a nitro group, NR⁹R¹⁰ {wherein R⁹ and R¹⁰ are the same or different, and each has the same meaning as R¹, or represents SO₂R^(3E) (wherein R^(3E) has the same meaning as R³) or CQ^(B)BR¹¹ (wherein Q^(B) has the same meaning as Q; and R¹¹ has the same meaning as R¹, or represents OR^(3F) (wherein R^(3F) has the same meaning as R³) or NR^(1C)R^(1D) (wherein R^(1C) and R^(1D) are the same or different, and each has the same meaning as R¹, or R^(1C) and R^(ID) are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group)), or R⁹ and R¹⁰ are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group}, CQ^(C)R^(11A) (wherein Q^(C) has the same meaning as Q; and R^(11A) has the same meaning as R¹¹), OR¹² {wherein R¹² has the same meaning as R¹, or represents CQ^(D)R¹³ (wherein Q^(D) has the same meaning as Q; and R¹³ has the same meaning as R¹, or represents OR^(3G) (wherein R^(3G) has the same meaning as R³), SR^(3H) (wherein R^(3H) has the same meaning as R³), or NR^(1E)R^(1F) (wherein R^(1E) and R^(1F) are the same or different, and each has the same meaning as R¹, or R^(1E) and R^(1F) are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group)), or SO²R^(3I) (wherein R^(3I) has the same meaning as R³)}, SR^(1G) (wherein R^(1G) has the same meaning as R¹), SOR^(3J) (wherein R^(3J) has the same meaning as R³) or SO₂R¹⁴ (wherein R¹⁴ has the same meaning as R³, or represents OR^(1H) (wherein R^(1H) has the same meaning as R¹) or NR^(1I)R^(1J) (wherein R^(1I) and R^(IJ) are the same or different, and each has the same meaning as R¹, or R^(1I) and R^(1J) are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group ))>, and (1) when V represents N—R⁶ or CR⁷R⁸, and U represents NR¹R², OR⁴, or SR⁵ D¹, D², D³ and D⁴ each independently represent C—R^(B) (wherein R^(B) has the same meaning as R^(A)), a nitrogen atom, an oxygen atom, or a sulfur atom: or optional adjoining two among D¹ to D⁴ maybe combined to represent a nitrogen atom, N—R^(2A) (wherein R^(2A) has the same meaning as R² described above, or represents an alkyl group or CQ^(E)NHR^(3K) (wherein Q^(E) has the same meaning as Q and R^(3K) has the same meaning as R³), an oxygen atom, or a sulfur atom, and the remains among D¹ to D⁴ may represent C—R^(B′) (wherein R^(B′) has the same meaning as R^(A)), N—R^(2A′) (wherein R^(2A′) has the same meaning as R^(2A)), or a nitrogen atom; and in these two cases, the optional adjoining two selected from D¹ to D⁴ may represent C—R^(B″) (wherein two R^(B″)s, together with the two adjoining carbon atoms, represent an optionally substituted alkene selected from the group consisting of cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and cyclododecene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted imidazol-2-one, substituted or unsubstituted imidazole-2-thione, substituted or unsubstituted triazole, substituted or unsubstituted furan, substituted or unsubstituted 1,3-dioxole, substituted or unsubstituted 1,4-dioxene, substituted or unsubstituted thiophene, substituted or unsubstituted oxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted triazine, substituted or unsubstituted tetrazine, or substituted or unsubstituted benzene), and (2) when V represents an oxygen atom or a sulfur atom, and U represents NR¹R², (2-1) at least one of D¹ to D⁴ represents a nitrogen atom, an oxygen atom or a sulfur atom; optional adjoining two among D¹ to D⁴ are combined to represent a nitrogen atom, N—R^(2B) (wherein R^(2B) has the same meaning as R²), or an oxygen atom; or D² and D³ are combined to represent a sulfur atom; and in these three cases, the remains among D¹ to D⁴ represent a nitrogen atom, N—R^(2B′) (wherein R^(2B′) has the same meaning as R²), an oxygen atom, a sulfur atom, or C—R^(C) (wherein the R^(C)s each independently have the same meaning as R^(A), or optional two R^(C)s′ adjoining adjacent carbon atoms, together with the two adjoining carbon atoms, may represent an optionally substituted alkene selected from the group consisting of cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and cyclododecene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted imidazol-2-one, substituted or unsubstituted imidazole-2-thione, substituted or unsubstituted triazole, substituted or unsubstituted furan, substituted or unsubstituted 1,3-dioxole, substituted or unsubstituted 1,4-dioxene, substituted or unsubstituted oxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiophene, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted triazine, substituted or unsubstituted tetrazine, or substituted or unsubstituted benzene, (2-2) D¹ and D² are combined to represent a sulfur atom; D³ represents C—R^(C) (wherein R^(C′) has the same meaning as R^(A)); and D⁴ represents a nitrogen atom, or D³ and D⁴ represent C—R^(C)″ (wherein R^(C)″s, together with two adjoining carbon atoms, represent an optionally substituted alkene selected from the group consisting of cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and cyclododecene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted imidazol-2-one, substituted or unsubstituted imidazole-2-thione, substituted or unsubstituted triazole, substituted or unsubstituted furan, substituted or unsubstituted 1,3-dioxole, substituted or unsubstituted 1,4-dioxene, substituted or unsubstituted oxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiophene, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted triazine, substituted or unsubstituted tetrazine, or substituted or unsubstituted benzene), (2-3) D³ and D⁴ are combined to represent a sulfur atom; D² represents C—R^(C″)′ (wherein R^(C′″) has the same meaning as R^(A)) ; and D¹ represents a nitrogen atom, or D¹ and D² represent C—R^(C)″″ (wherein R^(C″″) has the same meaning as R^(C)″), or (2-4) D¹, D², D³ and D⁴ represent C—R^(D) (wherein in R^(D)s, optional two R^(D)s′ adjoining adjacent carbon atoms, together with the two adjoining carbon atoms, represent an optionally substituted alkene selected from the group consisting of cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and cyclododecene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted isothiazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted triazine, or substituted or unsubstituted tetrazine, and each of the remaining R^(D)s independently represents the same meaning as R^(A)), or a pharmaceutically acceptable salt thereof.
 14. The nitrogen-containing heterocyclic compound according to claim 13, wherein W represents 1,4 piperazinediyl, or a pharmaceutically acceptable salt thereof.
 15. The nitrogen-containing heterocyclic compound according to claim 14, wherein at least one of X and Z represents a nitrogen atom; and Y represents C—R^(A), or a pharmaceutically acceptable salt thereof.
 16. The nitrogen-containing heterocyclic compound according to claim 15, wherein X and Z each represent a nitrogen atom; and R^(A) represents a hydrogen atom or NR⁹R¹⁰, or a pharmaceutically acceptable salt thereof.
 17. The nitrogen-containing heterocyclic compound according to claim 16, wherein U represents NR¹R², or a pharmaceutically acceptable salt thereof.
 18. The nitrogen-containing heterocyclic compound according to claim 17, wherein R¹ represents a hydrogen atom; and R² represents a hydrogen atom, a substituted alkyl group, a substituted or unsubstituted group (said group being selected from monocyclic groups having from 3 to 12 carbon atoms, pinanyl, 1,7,7-trimethylbicyclof[2.2.1]heptyl, adamantyl, hexahydro-4,7-methano-1H-indenyl and 4-hexylbicyclo[2.2.2]octyl), an optionally substituted heterocyclic group selected from the group consisting of tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl and thiomorpholinyl, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group, or a pharmaceutically acceptable salt thereof.
 19. The nitrogen-containing heterocyclic compound according to claim 18, wherein R² represents a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group, or a pharmaceutically acceptable salt thereof.
 20. The nitrogen-containing heterocyclic compound according to claim 19, wherein V represents N—R⁶; and 1) D¹ and D² are combined to represent N—R^(2A); and D³ and D⁴ each independently represent C—R^(B′), 2) D¹ and D² each independently represent C—R^(B′); and D³ and D⁴ are combined to represent N—R^(2A), 3) D¹ and D⁴ each independently represent C—R^(B′); and D² and D³ are combined to represent N—R^(2A), 4) D¹ represents C—R^(B′); D² and D³ are combined to represent a nitrogen atom; and D⁴ represents N—R^(2A′), 5) D⁴ represents C—R^(B′); D² and D³ are combined to represent a nitrogen atom; and D¹ represents N—R^(2A′), 6) D¹ and D² are combined to represent N—R^(2A); D³ represents C—R^(B′); and D⁴ represents a nitrogen atom, 7) D¹ and D² are combined to represent a nitrogen atom; D³ represents C—R^(B′); and D⁴ represents N—R^(2A′), 8) D¹, D² and D³ each independently represent C—R^(B); and D⁴ represents a nitrogen atom, 9) D¹, D² and D⁴ each independently represent C—R^(B); and D³ represents a nitrogen atom, 10) D¹, D³ and D⁴ each independently represent C—R^(B); and D² represents a nitrogen atom, 11) D², D³ and D⁴ each independently represent C—R^(B); and D¹ represents a nitrogen atom, 12) D¹ and D³ represent nitrogen atoms; and D² and D⁴ each independently represent C—R^(B), 13) D¹ and D³ each independently represent C—R⁸ ; and D² and D² represent nitrogen atoms, 14) D¹ and D² each independently represent C—R^(B); and D² and D⁴ represent nitrogen atoms, 15) D¹ and D² each independently represent C—R^(B); and D² and D³ represent nitrogen atoms, 16) D³ and D⁴ each independently represent C—R^(B); and D¹ and D² represent nitrogen atoms, 17) D² and D³ each independently represent C—R^(B); and D¹ and D⁴ represent nitrogen atoms, 18) D¹, D², D³ and D⁴ each independently represent C—R^(B), 19) D¹ and D² each independently represent C—R^(B′); and D³ and D⁴ are combined to represent a sulfur atom, 20) D¹ and D⁴ each independently represent C—R^(B′); and D² and D³ are combined to represent a sulfur atom, or 21) D³ and D⁴ each independently represent C—R^(B′); and D¹ and D² are combined to represent a sulfur atom, or a pharmaceutically acceptable salt thereof.
 21. The nitrogen-containing heterocyclic compound according to claim 19, wherein V represents an oxygen atom or a sulfur atom; and 1) D¹ and D² are combined to represent N—R^(2B); and D³ and D⁴ each independently represent C—R^(C), 2) D¹ and D² each independently represent C—R^(C), and D³ and D⁴ are combined to represent N—R^(2B), 3) D¹ and D⁴ each independently represent C—R^(C) and D² and D³ are combined to represent N—R^(2B), 4) D¹ represents C—R^(C); D² and D³ are combined to represent a nitrogen atom; and D⁴ represents N—R^(2B′), 5) D⁴ represents C—R^(C); D² and D³ are combined to represent a nitrogen atom; and D¹ represents N—R^(2B′), 6) D¹ and D² are combined to represent N—R^(2B); D³ represents C—R^(C); and D⁴ represents a nitrogen atom, 7) D¹ and D² are combined to represent a nitrogen atom; D³ represents C—R^(C); and D⁴ represents N—R^(2B′), 8) D¹, D² and D³ each independently represent C—R^(C); and D⁴ represents a nitrogen atom, 9) D¹, D² and D⁴ each independently represent C—R^(C); and D³ represents a nitrogen atom, 10) D¹, D³ and D⁴ each independently represent C—R^(C); and D² represents a nitrogen atom, 11) D², D³ and D⁴ each independently represent C—R^(C); and D¹ represents a nitrogen atom, 12) D¹ and D³ represent nitrogen atoms; and D² and D⁴ each independently represent C—R^(C), 13) D¹ and D³ each independently represent C—R^(C); and D² and D⁴ are nitrogen atoms, 14) D¹ and D² each independently represent C—R^(C); and D³ and D⁴ are nitrogen atoms, 15) D¹ and D⁴ each independently represent C—R^(C); and D² and D³ are nitrogen atoms, 16) D³ and D⁴ each independently represent C—R^(C) and D¹ and D² are nitrogen atoms, 17) D² and D³ each independently represent C—R^(C); and D¹ and D⁴ are nitrogen atoms, 18) D¹, D², D³ and D⁴ each independently represent C—R^(D), 19) D¹ and D⁴ each independently represent C—R^(C″″); and D³ and D⁴ are combined to represent a sulfur atom, 20) D¹ and D⁴ each independently represent C—R^(C); and D² and D³ are combined to represent a sulfur atom, or 21) D³ and D⁴ each independently represent C—R^(C)″; and D¹ and D² are combined to represent a sulfur atom, or a pharmaceutically acceptable salt thereof.
 22. The nitrogen-containing heterocyclic compound according to claim 20, wherein R⁶ represents CN; and 1) D¹ and D² are combined to represent a nitrogen atom; represents C—R^(B′); and D⁴ represents N—R^(2A′), 2) D¹, D² and D⁴ each independently represent C—R^(B); and D³ represents a nitrogen atom, or 3) D¹, D², D³ and D⁴ each independently represent C—R^(B), or a pharmaceutically acceptable salt thereof.
 23. The nitrogen-containing heterocyclic compound according to claim 21, 1) D¹ and D² are combined to represent a nitrogen atom; D³ represents C—R^(C); and D⁴ represents N—R^(2B′), 2) D¹, D² and D⁴ each independently represent C—R^(C); and D³ represents a nitrogen atom, or 3) D¹, D², D³ and D⁴ each independently represent C—R^(D), or a pharmaceutically acceptable salt thereof.
 24. The nitrogen-containing heterocyclic compound according to claim 19, wherein V represents an oxygen atom or a sulfur atom; D¹, D², D³ and D⁴ represent C—R^(D); and optional two R^(D)s^(′) adjoining adjacent carbon atoms, together with the two adjoining carbon atoms, represent substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, or substituted or unsubstituted pyrazine, or a pharmaceutically acceptable salt thereof. 